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Head and neck tumor organoid biobank
2025
Goethe University Frankfurt, Frankfurt, Germany(1)
Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany(2)
Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany(2)
Head and neck cancers (HNCs) are a diverse group of tumors in the upper digestive and respiratory tracts, and it's often hard to know how they'll respond to treatment. Patient-derived tumor organoids (PDTOs), which are tiny 3D models of tumors grown from patient tissue, could help personalize treatment. In this study, researchers developed a collection of these organoid models, called a head and neck organoid biobank (HNOB), that represents the major clinically relevant subtypes of HNC, specifically those driven by mutations in the TP53 gene and those caused by infection with human papillomavirus type 16 (HPV 16). Organoids were treated with radiation, and results linked to patient outcomes. Altered organoids showed how TP53 loss and HPV drive cancer.
The biobank has 18 organoids. Organoids showed gene patterns linked to cancer types and different responses to a TP53 drug. How organoids reacted to radiation matched patient responses and predicted relapse. TP53 loss and HPV increased growth, but only HPV made cells sensitive to radiation by blocking their cycle.
The results of this study demonstrate that organoid models of head and neck cancer represent a valuable tool for personalizing treatment decisions and for achieving a more detailed understanding of the molecular mechanisms that contribute to the development and progression of these cancers.
Head and neck tumor organoid biobank for modelling individual responses to radiation therapy according to the TP53/HPV status
Christian Issing(1), Henner F. Farin(2)
Christian Issing et al. Journal of Experimental & Clinical Cancer Research 2025 [1]
Biermann Medizin [2]
Added on: 04-30-2025
AI model for prostate tumor size and outcomes prediction
October 2024
Dana-Farber Cancer Institute, Boston, USA
Although MRI has improved the diagnosis of prostate cancer, estimates of tumour size by human clinicians can vary from person-to-person. Therefore, in this study, the researchers trained an AI model based on MRI images of prostate cancer tumours from 732 patients undergoing treatment at a single centre. Following this, the AI model’s size estimates were linked to treatment success in the five to 10 years after diagnosis. The researchers demonstrated that the AI model could locate and measure around 85 percent of prostate tumours that had a Prostate Imaging Reporting and Data System (PI-RADS) score of 5 within the patient cohort. This score indicates a very high risk of clinically significant prostate cancer. Also, the model’s size estimates showed potential as a prognostic marker. For patients treated surgically or with radiation therapy, larger tumours were associated with higher risk that prostate cancer would come back, as measured by blood levels of prostate-specific antigen (PSA).
AI-derived tumor volume from multiparametric MRI and outcomes in localized prostate cancer
Martin T. King
Added on: 12-03-2024
Autoantibody predicts survival of patients with hepatocellular carcinoma
2024
Okayama University Graduate School of Medicine, Okayama, Japan
This study investigated serum anti-PD-1 autoantibody levels as potential biomarkers for predicting the efficacy of atezolizumab and bevacizumab combination therapy (Atezo/Bev) in advanced hepatocellular carcinoma (HCC) patients. In a prospective study of 63 patients, serum anti-PD-1 autoantibody levels were measured before treatment. While not significantly associated with treatment response overall, higher antibody levels correlated with worse overall survival rates in first-line therapy patients. The antibody titer was identified as an independent risk factor for poor prognosis, along with higher neutrophil-to-lymphocyte ratio and lower albumin levels. These findings suggest that serum anti-PD-1 autoantibody levels may serve as a biomarker for predicting immune checkpoint inhibitor efficacy in HCC patients.
Anti-PD-1 autoantibody predicts survival of patients with hepatocellular carcinoma receiving atezolizumab/bevacizumab
Akinobu Takaki
Added on: 12-03-2024
Bone-on-a-chip for osteoporotic bone metastasis
2024
Dongguk University, Goyang, South Korea
In this study, a bone-on-a-chip system was developed to replicate the human bone microenvironment. The chip was fabricated using soft silicone molding and featured distinct vascular and bone compartments. Osteoblasts, osteocytes, and osteoclasts were co-cultured within a fibrin-based extracellular matrix, using specific cell ratios to model normal, osteopenic, and osteoporotic conditions. Mineralization and cell morphology were assessed using calcein staining and image analysis. Vascular permeability was also evaluated. To simulate bone metastasis, breast cancer cells were introduced, and their migration was tracked. The results showed that metastasis was most active under osteoporotic conditions, correlating with increased vascular permeability. This bone-on-a-chip system provides a promising platform for drug testing and for studying the mechanisms underlying bone diseases and metastasis.
Bone-on-a-chip simulating bone metastasis in osteoporosis
Bong Seop Kwak
Added on: 05-15-2025
Human organoids with autologous immune cells
2024
Institute of Human Biology (IHB), Basel, Switzerland
The epithelium-immune system relationship is crucial for maintaining tissue health, with disruptions linked to autoimmune diseases and cancer. While stem cell-derived organoids are valuable models for studying epithelial function, they lack immune cells required for organ-level processes. This study developed human intestinal immuno-organoids (IIOs) by combining epithelial organoids with autologous tissue-resident memory T (TRM) cells, a portion of which integrate into the epithelium and monitor the barrier. Using IIOs and single-cell transcriptomics, intestinal inflammation triggered by cancer-targeting biologics was studied, revealing activation of CD8+ T cells and a CD4+ T helper-1-like population. The Rho pathway was identified as a potential target to mitigate immunotherapy-associated intestinal inflammation, highlighting IIOs as a valuable tool for studying immune responses in cancer and autoimmune diseases.
Human organoids with an autologous tissue-resident immune compartment
Nikolche Gjorevski, Jarrett Gray Camp, Lauriane Cabon
Added on: 11-06-2024
Spatial relationships of immune and cancer cells in colorectal cancer
2024
GE HealthCare Technology and Innovation Center, Niskayuna, USA(1)
Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland(2)
Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland(2)
This study explored the spatial relationships between T cells, cancer cells, and cancer cell characteristics as potential prognostic biomarkers in stage III colorectal cancer patients treated with adjuvant chemotherapy. Using advanced imaging techniques, the researchers analysed protein markers at the single-cell level in tissue samples from two patient cohorts. They developed a method to measure the spatial proximity between different cell types. While the overall percentage of cytotoxic T cells did not significantly predict outcomes, shorter distances between cytotoxic T cells, helper T cells, and cancer cells were linked to better disease-free survival in both cohorts. An unsupervised model based on these spatial relationships and protein expression profiles successfully classified patients into low-risk and high-risk groups for recurrence. This research indicates that the spatial arrangement of immune and cancer cells may serve as a valuable prognostic tool in colorectal cancer.
Spatial effects of infiltrating T cells on neighbouring cancer cells and prognosis in stage III CRC patients
Fiona Ginty(1), Jochen HM Prehn(2)
Added on: 01-02-2025
Unannotated RNAs as promising biomarkers for prostate cancer
2024
Icahn School of Medicine at Mount Sinai, New York, USA
Extracellular vesicles (EVs) are secreted by all cells and play important roles in communication and waste disposal. This study explores small unannotated RNAs from EVs, which may regulate gene expression and serve as potential biomarkers for prostate cancer. The researchers created an innovative bioinformatic pipeline to analyse RNA data from prostate cancer and benign tissues, revealing distinct expression patterns linked to unannotated genomic regions, termed "EV-UGRs." These EV-UGRs were significantly downregulated in the serum of patients with aggressive prostate cancer but were upregulated after radical prostatectomy. A new assay was developed to validate these findings for use in non-invasive diagnostics. Overall, this research highlights the potential of EV-UGRs as promising biomarkers for prostate cancer.
Extracellular vesicles carry transcriptional ‘dark matter’ revealing tissue-specific information
Gustavo Stolovitzky, Navneet Dogra
Added on: 12-19-2024
Dabrafenib in 2D vs 3D melanoma models
2024
University of Malta, Msida, Malta
Melanoma, the most lethal form of skin cancer, remains a major clinical challenge due to the lack of effective early treatment models. This study investigated the impact of the BRAF inhibitor dabrafenib on melanoma by applying a high-throughput workflow for drug screening to both 2D and 3D cell culture models. Metastatic melanoma cells with the BRAF V600E mutation and normal melanocytes were cultured in 2D monolayers and 3D spheroids, and treated with varying concentrations of dabrafenib. A series of in vitro assays was conducted to assess the effects on cell viability, aggregation, migration, cell cycle progression, and apoptosis. Dabrafenib was shown to reduce cell viability, inhibit cellular adhesion and aggregation, impede migration, induce G1 cell cycle arrest, and promote apoptosis, particularly in the melanoma cell line. These results confirm the therapeutic potential of dabrafenib in treating melanoma with the BRAF V600E mutation, and demonstrate that 3D models are validated systems for studying new molecules for therapeutic purposes.
Comparative analysis of the effect of the BRAF inhibitor dabrafenib in 2D and 3D cell culture models of human metastatic melanoma cells
Marion Zammit-Mangion, David Tovar-Parra
Added on: 08-05-2024
Co-cultivation of human macrophages with breast cancer tumoroids
2024
Université Lille, Lille, France
3D tumoroids have revolutionized in vitro/ex vivo cancer biology by recapitulating the complex diversity of tumors. While tumoroids provide new insights into cancer development and treatment response, several limitations remain. As the tumor microenvironment, especially the immune system, strongly influences tumor development, the absence of immune cells in tumoroids may lead to inappropriate conclusions. Macrophages, key players in tumor progression, are particularly challenging to integrate into the tumoroids. In this study, three optimized and standardized methods for co-culturing human macrophages with breast cancer tumoroids were established: a semi-liquid model and two matrix-embedded models tailored for specific applications. Interactions and macrophage infiltration were tracked in these systems using flow cytometry and light sheet microscopy. It was shown that macrophages influenced not only tumoroid molecular profiles but also chemotherapy response. This underscores the importance of increasing the complexity of 3D models to more accurately reflect in vivo conditions.
A co-culture system of macrophages with breast cancer tumoroids to study cell interactions and therapeutic responses
Michel Salzet, Marie Duhamel
Added on: 07-01-2024
Systematic biases in reference-based plasma cell-free DNA fragmentomic profiling
2024
Shenzhen Bay Laboratory, Shenzhen, China
Plasma cell-free DNA (cfDNA) fragmentation patterns are emerging directions in cancer liquid biopsy with high translational significance. Conventionally, the cfDNA sequencing reads are aligned to a reference genome to extract their fragmentomic features. In this study, through cfDNA fragmentomics profiling using different reference genomes on the same datasets in parallel, systematic biases in such conventional reference-based approaches were reported. The biases in cfDNA fragmentomic features vary among ancestries in a sample-dependent manner, and therefore might adversely affect the performances of cancer diagnosis assays across multiple clinical centres. In addition, to circumvent the analytical biases, Freefly was developed, a reference-free approach for cfDNA fragmentomics profiling. Freefly runs ∼60-fold faster than the conventional reference-based approach while generating highly consistent results. Moreover, cfDNA fragmentomic features reported by Freefly can be directly used for cancer diagnosis. Hence, Freefly possesses translational merit toward the rapid and unbiased measurement of cfDNA fragmentomics.
Systematic biases in reference-based plasma cell-free DNA fragmentomic profiling
Kun Sun
Added on: 07-08-2024
Subtype-WGME enables whole-genome-wide, multi-omics cancer subtyping
2024
East China University of Science and Technology, Shanghai, China
In this study, an innovative strategy for integrating whole-genome-wide multi-omics data is presented, which facilitates adaptive amalgamation by leveraging hidden layer features derived from high-dimensional omics data through a multi-task encoder. Empirical evaluations on eight benchmark cancer datasets substantiated that the proposed framework outstripped the comparative algorithms in cancer subtyping, delivering superior subtyping outcomes. Building upon these subtyping results, a robust pipeline for identifying whole-genome-wide biomarkers was established, unearthing 195 significant biomarkers. Furthermore, an exhaustive analysis to assess the importance of each omic and non-coding region features at the whole-genome-wide level during cancer subtyping was conducted. The investigation shows that both omics and non-coding region features substantially impact cancer development and survival prognosis. This study emphasizes the potential and practical implications of integrating genome-wide data in cancer research, demonstrating the potency of comprehensive genomic characterization. Additionally, the findings offer insightful perspectives for multi-omics analysis employing deep learning methodologies.
Subtype-WGME enables whole-genome-wide multi-omics cancer subtyping
Zhe Wang
Added on: 07-08-2024
Liver-on-a-chip for immunotherapy testing
2024
University of Birmingham, Birmingham, United Kingdom
Immunotherapy has changed the landscape of treatment options for patients with hepatocellular cancer. Checkpoint inhibitors are now standard of care for patients with advanced tumours, yet the majority remain resistant to this therapy and urgent approaches are needed to boost the efficacy of these agents.
Targeting the liver endothelial cells, as the orchestrators of immune cell recruitment, within the tumour microenvironment of this highly vascular cancer could potentially boost immune cell infiltration. In this work, the successful culture of primary human liver endothelial cells in organ-on-a-chip technology followed by perfusion of peripheral blood mononuclear cells was demonstrated. The authors confirm, with confocal and multiphoton imaging, the capture and adhesion of immune cells in response to pro-inflammatory cytokines in this model. This multicellular platform sets the foundation for testing the efficacy of new therapies in promoting leukocyte infiltration across liver endothelium as well as a model for testing cell therapy, such as chimeric antigen receptor (CAR)-T cell, capture and migration across human liver endothelium.
Organ-on-a-chip for studying immune cell adhesion to liver sinusoidal endothelial cells: the potential for testing immunotherapies and cell therapy trafficking
Shishir Shetty
Added on: 12-10-2024
AI-powered algorithm accelerates TCR identification to develop personalized immunotherapies
2024
German Cancer Research Center, Heidelberg, Germany
To accelerate the development of personalized T cell therapies, an antigen-independent classifier (predicTCR) is presented in the present study. PredicTCR is a machine learning algorithm that leverages high-performance single-TIL RNA sequencing techniques to identify reactive T cell receptors (TCRs) in tumor-infiltrating lymphocyte cultures (TILs) of various cancer types. The resected tumor tissue used for the study was provided by a male 62-year-old melanoma patient. After successfully identifying reactive TCRs in the donor's tumor samples, the researchers used the results and other sequence data to train the algorithm. The results show that predicTCR's predictions have significantly higher accuracy (up to 90%) and sensitivity than previous methods. Additionally, the combination of high-throughput TCR cloning and reactivity validation enables selection of prioritized TCR clonotypes in just a few days. In summary, the method proves to be an innovative and efficient approach that can help optimize the production of personalized immunotherapies by saving valuable time and continuously specifying and improving the search for reactive TCRs through the integrated machine learning system.
Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy
E. W. Green, M. Platten
Added on: 04-02-2024
Organ-on-a-Chip system for simulated microgravity
2024
Latvian Biomedical Research and Study Centre, Riga, Latvia
The study describes the development of a new microfluidic system in which human cells grow and are continuously perfused with fluid. It was designed to function under reduced gravity. To achieve this, the system was tested in a rotation unit that simulates gravity conditions similar to those in space. Human cancer cells were cultured in the system, and it was found that the cells showed reduced growth under decreased gravity.
The chip can be used to better understand how diseases or medications behave under space conditions. It helps researchers gain new insights without having to travel to space and improves the understanding of cellular behavior in special environments.
Development of organ-on-a-chip system with continuous flow in simulated microgravity
Arnis Strods
Added on: 05-15-2025
Micro- and nanoplastic particles promote the cell proliferation of colon cancer cells
2024
Medical University of Vienna, Vienna, Austria(1)
University of Vienna, Vienna, Austria(2)
University of Vienna, Vienna, Austria(2)
In the present study, researchers developed 2D and 3D models from human colon cancer cell lines to further study the effects of micro- and nanoplastic particles (MNPs) on the gastrointestinal tract (GIT). The models were exposed to MNPs at different concentrations and sizes (0.25, 1 and 10 μm) for 72 hours and then analysed using various in vitro methods. The researchers were able to show that the plastic particles were taken up by all four colon cancer cell lines used (HT29, HCT116, SW480 and SW620). The absorption rate was significantly dependent on the size and concentration of the MNPs. Furthermore, it was observed that the plastic particles persisted in the lysosomes of the cells and were transferred to the daughter cells through cell division. In particular, the smallest particles (0.25 μm) significantly increased cell migration and appeared to promote the spread of metastases. In addition, an enrichment of MNPs was found in the non-proliferating areas of the tumor spheroids, although this did not affect the proliferation and division of the cells. According to the REACH regulation, the persistence and accumulation of microplastic particles are among the most important toxicological characteristics of chemical substances. The results therefore emphasize the importance of the need for further research into MNPs as catalysts for the growth and spread of tumor cells, as well as other potentially harmful influences on humans and the environment.
Microplastics role in cell migration and distribution during cancer cell division
Lukas Kenner(1), Verena Pichler(2)
Added on: 03-13-2024
Blood test for neuroendocrine prostate cancer
2024
Dana Farber Cancer Institute, Boston, USA(1)
University of Trento, Trento, Italy(2)
University of Trento, Trento, Italy(2)
Neuroendocrine prostate cancer is an aggressive subtype of treatment-resistant prostate cancer. Early detection is important, but the diagnosis currently relies on metastatic biopsy. Here, the researchers used patient plasma samples to develop a blood test that reliably detects neuroendocrine prostate cancer and can differentiate it from castration-resistant prostate adenocarcinoma. The test consists of a plasma cell–free DNA targeted methylation panel that can quantify tumor fraction and identify patients with neuroendocrine prostate cancer noninvasively. The results were associated with clinical outcomes in two prospective phase II clinical trials.
Noninvasive detection of neuroendocrine prostate cancer through targeted cell-free DNA methylation
Himisha Beltran(1), Francesca Demichelis(2)
Added on: 01-26-2024
Influence of cancer medications on COVID-19
2024
University of Zagreb, Zagreb, Croatia
People with lymphoid malignancies (such as lymphomas) have an increased risk of dying from COVID-19 or remaining infected for an extended period. This retrospective study examines the impact of different cancer therapies on the course of infection. An analysis of 314 patients with lymphoid malignancies who contracted COVID-19 between October 2020 and April 2021 revealed significant differences depending on treatment status. In the group of patients currently undergoing treatment, the mortality rate was significantly higher (35%) compared to patients who had completed therapy (15%).
The results show that age and certain medications (such as purine analogues) are key factors that increase the risk of a severe or prolonged course of COVID-19 in patients with lymphoid malignancies.
Treatment-related risk factors for adverse outcomes of COVID-19 in patients treated for lymphoid malignancies in the pre-omicron era—A study of KroHem, the Croatian group for hematologic diseases
Igor Aurer
Added on: 05-15-2025
AI uses chromatin as a biomarker for the (early) diagnosis and treatment evaluation of cancer
December 2023
Paul-Scherrer Institute, Villigen, Switzerland
Results of previous studies show that tumors influence the chromatin conformation in peripheral blood mononuclear cells (PBMCs) through so-called secretome signals. In addition, the concentration of the secretomes depends on the stage of the disease. Following this, the present study evaluates the potential of chromatin biomarkers for early diagnosis and treatment evaluation of cancer. For this purpose, the three-dimensional chromatin organization from blood samples from 10 healthy volunteers and various tumor patients was first imaged and analysed using fluorescence methods. Characteristic chromatin patterns and features were transformed into subject-specific data sets and fed into a machine learning system for prediction. In a first series of tests, the data sets from 10 healthy volunteers were compared with the information from 10 tumor patients. The AI was able to distinguish between healthy and sick people with a high level of sensitivity based on the chromatic characteristics. In further series of tests, it was also shown that the AI could distinguish three tumor groups from one another with up to 89% accuracy. Finally, the chromatin conformation of 30 tumor patients (10 glioma, 10 meningioma and 10 head and neck tumor patients) who underwent proton irradiation was examined. The blood samples were taken and analysed at three different stages during therapy. The results showed characteristic cellular changes that indicated a response to therapy and will be further developed in future clinical studies. In summary, the AI-based chromatin biomarker analysis proves to be a new and valuable method that can help to diagnose cancer at an early stage, to predict the success or response of patient-specific therapeutic approaches and to avoid the use of invasive diagnostic procedures in seriously ill patients.
Imaging and AI based chromatin biomarkers for diagnosis and therapy evaluation from liquid biopsies
Damien C. Weber, damien.weber@psi.ch
Added on: 12-19-2023
Organoids to analyse the off-tumour toxicity of T-cell-engaging bispecific antibodies
December 2023
Roche Innovation Center Basel, Basel, Switzerland
Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the expression of relevant human antigens. Here, it was shown that patient-derived intestinal organoids and tumouroids supplemented with immune cells can be used to study the on-target off-tumour toxicities of T-cell-engaging bispecific antibodies (TCBs), and to identify clinical toxicities not predicted by conventional tissue-based models as well as inter-patient variabilities in TCB responses. The mechanisms of T-cell-mediated damage to neoplastic and donor-matched healthy epithelia at a single-cell resolution were analysed using multiplexed immunofluorescence. It was found that TCBs that target the epithelial cell-adhesion molecule led to apoptosis in healthy organoids in accordance with clinical observations, and that apoptosis is associated with T-cell activation, cytokine release and intra-epithelial T-cell infiltration. Conversely, tumour organoids were more resistant to damage, probably owing to a reduced efficiency of T-cell infiltration within the epithelium. Patient-derived intestinal organoids can aid the study of immune–epithelial interactions as well as the preclinical and clinical development of cancer immunotherapies.
Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids
Nikolche Gjorevski
Added on: 02-16-2024
Personalized organoid drug testing predicts colorectal cancer treatment response
December 2023
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Predictive drug testing of patient-derived tumor organoids (PDTOs) holds promise for personalizing treatment of metastatic colorectal cancer (mCRC), but prospective data are limited to chemotherapy regimens with conflicting results. Here the researchers describe a unified framework for PDTO-based predictive testing across standard-of-care chemotherapy and biologic and targeted therapy options. In an Australian community cohort, PDTO predictions based on treatment-naive patients (n = 56) and response rates from first-line mCRC clinical trials achieve 83% accuracy for forecasting responses in patients receiving palliative treatments (18 patients, 29 treatments). Similar assay accuracy is achieved in a prospective study of third-line or later mCRC treatment (n = 30 patients). “Resistant” predictions are associated with inferior progression-free survival; misclassification rates are similar by regimen. Liver metastases are the optimal site for sampling, with testing achievable within 7 weeks for 68.8% cases. These findings indicate that PDTO drug panel testing can provide predictive information for multifarious standard-of-care therapies for mCRC.
Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer
Oliver M. Sieber
Added on: 04-02-2024
Brain metastasis-on-a-chip
October 2023
Seoul National University, Seoul, South Korea
The human brain choroid plexus (ChP) is a secretory tissue separating blood from the crerebrospinal fluid (CSF) thereby functioning as the blood-CSF barrier.
In this study, the ChP structure is recapitulated by developing a microfluidic chip which is used to culture human ChP cells. The brain extracellular matrix is mimicked by using a hydrogel and CSF flow dynamics by rocking the system. The use of the ChP-on-a-chip in drug screening is demonstrated by observing physiologically relevant drug responses from breast cancer cells that had spread in the ChP. ChP immune responses are also recapitulated, as demonstrated by the motility and cytotoxic effects of macrophages.
The human ChP-on-a-chip will facilitate the elucidation of ChP pathophysiology and support the development of therapeutics to treat cancers that have metastasized into the ChP.
Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis
Noo Li Jeon
Added on: 09-11-2023
Immunosensor for the detection of HSP70
October 2023
China Medical University Hospital, Taichung, Taiwan
The aim of this study was the development of a non-invasive cancer biomarker sensor that offers high accuracy, low cost, and is time-saving. The electrochemical immunosensor design strategy involves the immobilization of an anti-HSP70 antibodies on a nanocomposite-modified electrode via chemical coupling.
Impedance measurements of HSP70 on the developed immunosensor showed an increase in impedance with an increase in HSP70 concentration. The immunosensor was also effective in detecting HSP70 at very low concentrations in a lung adenocarcinoma cell line and to monitor changes of the HSP70 concentration following Paclitaxel treatment.
The developed sensor holds the potential to detect the HSP70 biomarker in organ-on-a-chip and clinical applications.
A novel label-free electrochemical immunosensor for the detection of heat shock protein 70 of lung adenocarcinoma cell line following paclitaxel treatment using L-cysteine-functionalized Au@MnO2/MoO3 nanocomposites
Yi-Wen Chen
Added on: 12-09-2023
Model for radiation-induced lung injury
October 2023
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, USA
Acute exposure to high-dose gamma radiation due to cancer radiotherapy can result in radiation-induced lung injury (RILI). In this study, a human lung-on-a-chip model is used to investigate acute RILI in vitro. Therefore, a 2-channel chip obtained by Emulate Inc. was used to cultivate human lung alveolar epithelial cells under an air-liquid interface (ALI) and a human lung microvascular endothelium was included. Cyclic mechanical strain was applied to mimic the breathing motions and in some of the experiments human immune cells (human peripheral blood mononuclear cells) were introduced in the vascular channel.
Both, lung epithelium and endothelium exhibit DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6 h of radiation exposure. The radiation dose sensitivity observed on the chip is more like the human lung than that observed in preclinical in vivo models. Moreover, the ability of two drugs to suppress the effects of acute RILI was investigated.
The Lung Alveolus Chip provides a human relevant model for studying the molecular basis of acute RILI and can be useful for evaluation of radiation countermeasure therapeutics.
A human lung alveolus-on-a-chip model of acute radiation-induced lung injury
Donald E. Ingber
Added on: 12-02-2023
Autoantibodies in pancreatic ductal adenocarcinoma
2023
Cold Spring Harbor Laboratory, New York, USA
Over 90 percent of pancreatic cancer cases are recognised as an aggressive, fatal form of the disease known as pancreatic ductal adenocarcinoma (PDAC). In this study, the researchers planned to discover a novel antigen found in PDAC tumours only. Detecting a new PDAC antigen may aid explanations of why some patients have more favourable outcomes than others. The authors used single-cell RNA sequencing (scRNA-Seq) and immunoglobulin (Ig) sequencing of tumor-infiltrating immune cells from 7 primary human PDAC samples. The results show that plasma cells in PDAC produce autoantibodies reacting with intracellular self-antigens, which may result from promotion of pre-existing, autoreactive B cell responses. These observations indicate the chronic inflammatory microenvironment of PDAC can support the adaptive immune response.
Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens
Douglas T. Fearon
Added on: 01-26-2024
Cholangiocarcinoma-on-a-chip for personalised medicine
2023
Humanitas University, Milan, Italy
Cholangiocarcinoma (CCA) is a primary liver tumour characterised by a poor prognosis and limited therapeutic options. Here, an innovative patient-specific cholangiocarcinoma (CCA)-on-chip platform was successfully developed, integrating the major components of the tumour microenvironment (tumour cells, cancer-associated fibroblasts, endothelial cells, and immune infiltrate) and faithfully mimicking the CCA niche. Primary CCA cells from 6 patients were used, and patient-specific reactions were measured in the chips. A drug trial showed the ability of the device to recapitulate different drug responses based on patient characteristics. This CCA-on-chip represents a powerful tool for unravelling disease-associated cellular mechanisms in CCA and provides an efficient tool for personalised drug testing.
Cholangiocarcinoma-on-a-chip: A human 3D platform for personalised medicine
Ana Lleo
Added on: 04-02-2024
Machine learning model identifies cancer-specific enhancer-gene interactions
2023
Weill Cornell Medicine, New York, USA
In this study, a computer model called Differential Gene Targets of accessible chromatin (DGTAC) was developed. It helps identify specific genetic areas that promote the growth of malignant cells, which is important for the development of anti-cancer drugs. The model uses data from 371 patients with different types of cancer to identify these areas. It only needs a small amount of tissue from the patients to make reliable predictions.
The model uses specific data (ATAC-seq and RNA-seq) to predict how genes are activated. It also takes into account other information such as the distance of the genetic sequences from their transcription start sites and how strongly they are activated. An important point in the predictions is a special error value that is calculated for each sample.
In tests with different cancer cells, the model was able to identify new areas that influence the activity of 602 cancer genes. In addition, the predictions of the model were checked and confirmed in experiments. The model can also distinguish different types of genetic regions, which previous methods could not.
The results of this study help us to better understand the genetic causes of diseases triggered by faulty gene activity. In addition, the model shows how it can be useful in developing tailored drugs for individual patients through its patient-specific approach.
Recapitulation of patient-specific 3D chromatin conformation using machine learning
Ekta Khurana
Added on: 09-26-2023
Reprogramming of cancer cells to hepatocytes
2023
Wake Forest University Health Sciences, Winston-Salem, USA
Lineage reprogramming is a technique to convert a functional cell type from one lineage to another lineage without passing through an intermediate pluripotent stage.
In this study, lineage conversion is performed for human breast cancer cells. Therefore, six transcriptional factors were introduced into lentiviral vectors and transduced into breast cancer cells. As a result, human induced hepatocyte-like cells (hiHeps) with hepatic phenotypes were obtained. Single cell sequencing was used to investigate the cells after reprogramming.
Moreover, a liver-on-a-chip (LOC) model was developed by 3D bioprinting of hepatocyte extracellular vesicles onto the microfluidic chip to assess the metastasis behaviour of the reprogrammed breast cancer cells. It was shown that the used transcription factors could reprogram the tumor cells into hiHeps, and thereby inhibit the metastasis of these cells.
It was shown that the LOC model could imitate the 3D liver microenvironment and be used to assess the behaviour of reprogrammed cancer cells as a potential treatment of metastatic cancers.
Detection of lineage-reprogramming efficiency of tumor cells in a 3D-printed liver-on-a-chip model
Weixin Zhao, Baisong Lu, Anthony Atala
Added on: 12-02-2023
Cellular atlas of the maternal-fetal interface
2023
Stanford University, Stanford, USA
This study aims to map the cellular interface between the placenta and the uterus in order to understand how cells from the fetus invade and remodel blood vessels in the lining of the uterus to ensure nutrient supply of the growing embryo.
500,000 cells from 588 uterine arteries derived from 66 individuals were analysed in a multi-omics approach. The derived spatiotemporal atlas of the human maternal-fetal interface will allow a deeper understanding of complications during pregnancy. Moreover, as many of the pathways involved in formation of the maternal-fetal interface are also involved in tumor progression, this atlas may help to understand how immune tolerance, tissue remodelling and angiogenesis are altered in cancer.
A spatially resolved timeline of the human maternal–fetal interface
Michael Angelo, Shirley Greenbaum
Added on: 08-21-2023
Colorectal cancer organoids for the analysis of fibroblast-tumor cell interactions
2023
Semmelweis University, Budapest, Hungary
Colorectal cancer (CRC) is a common disease and a leading cause of cancer-related deaths. An accumulation of cancer-associated fibroblasts (CAFs) causes tumor cells to become more aggressive and behave like stem cells, which indicates a poor prognosis. To explore the role of CAFs and potential treatments, this study used a patient-derived organoid model of CRC. Fibroblasts from tumor tissue of CRC patients were isolated and cultured together with the CRC organoids to analyse how these cells interact.
Using these organoid-based experiments, fibroblasts that produce high levels of the protein CD142 were identified. These fibroblasts stimulate the growth of CRC cells more than fibroblasts that produce low levels of CD142. They do this by releasing more of a growth factor called HGF. The effect of different combinations of cancer drugs on the cancer cells within the organoids was also studied. It was shown that a drug that inhibits the protein HSP90, namely PU-H71, mainly affected the CD142-producing fibroblasts. Both the cancer cells and the CAFs were sensitive to a drug that inhibits the protein BCL-XL, namely A-1155463 (BCLi).
The results from the organoid experiments suggest that the drugs A-1155463 (BCLi) and PU-H71 could be used to destroy cancer cells and reduce the number of CD142-producing CAFs that promote tumor growth. The use of CRC organoids made it possible to develop a strategy that aims to treat both cancer cells and stromal fibroblasts at the same time to prevent tumors from growing back.
High CD142 level marks tumor-promoting fibroblasts with targeting potential in colorectal cancer
Zoltán Wiener
Added on: 05-12-2025
Cryobiopsy for clinical utilization of lung cancer organoids
2023
Chungnam National University, Daejeon, South Korea
Until now, lung cancer organoids (LCOs) have mostly been obtained from surgical samples from patients with early stage lung cancer, as patients with advanced stages often cannot be operated. Biopsies are a solution, but conventional methods only yield small amounts of lung tissue, leading to a low success rate in culturing LCOs. Another critical issue is the overgrowth of normal lung cells in later passages of LCO culture, and the optimal culture conditions for LCOs have yet to be determined. To overcome these limitations, an attempt was made here to generate LCOs from cryobiopsy samples from patients with lung cancer. Overall, the initial success rate in generating LCOs from cryobiopsy samples was 40.7%. Transbronchial cryobiopsy allows the recovery of significantly larger amounts of lung tissue than bronchoscopic forceps biopsy. In addition, cryobiopsy can be used for peripheral lesions and is supported by radial endobronchial ultrasound. This study significantly improved the success rate of LCO culture and showed that the LCOs had features that resembled the primary tumours. Single-cell RNA sequencing confirmed high purity of cancer cells in early passages of LCOs derived from patients with advanced lung cancer. In addition, the three-dimensional structure and intracellular components of LCOs were characterised using three-dimensional holotomography. Finally, drug screening was performed using a dedicated micropillar culture system with LCOs obtained from cryobiopsy. LCOs obtained from cryobiopsy samples offer a promising solution to the critical limitations of conventional LCOs. Cryobiopsy can be used in patients with lung cancer at all stages, including those with peripheral lesions, and it can provide sufficient cells for LCO generation. Therefore one can assume that cryobiopsy will be a breakthrough strategy for the clinical application of LCOs in all stages of lung cancer.
Cryobiopsy: A breakthrough strategy for clinical utilization of lung cancer organoids
Chaeuk Chung
Added on: 08-31-2023
Prostate cancer-on-a-chip
2023
University Medicine Greifswald, Greifswald, Germany
The aim of this study was to develop a prostate cancer microphysiological system (PCa-MPS) model that recreates the epithelial nature of prostate cancers as well as their prostate-specific antigen (PSA) and miRNA secretion in vitro.
Androgen-sensitive (LNCaP) and androgen-insensitive (PC3) prostate cancer cells were grown in conventional and 3D cultures, both under static and dynamic conditions. Cell morphology, the secretion of PSA, and the expression of key prostate markers and microRNAs were analysed. LNCaP formed spheroids in 3D and MPS cultures, and maintained a constant PSA secretion in MPS. PC3 cells did not develop complex structures in 3D and MPS cultures.
This novel approach demonstrates that microRNA expression in prostate cancer cells is sensitive to external stimuli and that MPS can effectively promote important physiological changes in conventional prostate cancer models. The MPS model provides a new and more physiologically accurate tool for the study of PCa biomarkers for potential use in clinical practice and drug development applications.
Microfluidic‑based prostate cancer model for investigating the secretion of prostate‑specific antigen and microRNAs in vitro
Pedro Caetano Pinto
Added on: 09-11-2023
Ultrasound breast patch for deep tissue imaging
2023
Massachusetts Institute of Technology, Cambridge, USA
Ultrasound is widely used for tissue imaging such as breast cancer diagnosis; however, fundamental challenges limit its integration with wearable technologies, namely, imaging over large-area curvilinear organs. Here, the researchers introduced a wearable, conformable ultrasound breast patch (cUSBr-Patch) that enables standardized and reproducible image acquisition over the entire breast with less reliance on operator training and applied transducer compression. A nature-inspired honeycomb-shaped patch combined with a phased array is guided by an easy-to-operate tracker that provides for large-area, deep scanning, and multiangle breast imaging capability. The patch is designed to seamlessly integrate into a bra. The in vitro studies and clinical trials reveal that the array using a piezoelectric crystal exhibits a sufficient contrast resolution and axial/lateral resolutions at 30 mm depth, allowing the observation of small cysts (~0.3 cm) in the breast. This research develops a first-of-its-kind ultrasound technology for breast tissue scanning and imaging that offers a noninvasive method for tracking real-time dynamic changes of soft tissue.
Conformable ultrasound breast patch for deep tissue scanning and imaging
Canan Dagdeviren
Added on: 09-14-2023
3D co-culture model of hypopharyngeal cancer
2023
Newcastle University, Newcastle upon Tyne, United Kingdom
In this study, a tumor-stroma based in-vitro three-dimensional (3D)-tumoroid co-culture model of hypopharyngeal cancer (HPC) has been developed and investigated.
Therefore, a cell line derived from a human hypopharyngeal tumor (FaDu cell line) was co-cultured with a fibroblast-like human cell line (HS-5 cell line) to mimic the tumor-microenvironment. 3D-FaDu tumoroids were developed, as well as 3D-tumoroid co-cultures. Histology and immunostaining were done, and the growth kinetics of the 3D-tumoroids grown as monoculture as well as in co-culture were determined. The growth rate of the 3D tumoroid co-culture was found to be significantly higher compared to the tumoroid monoculture of FaDu. Moreover, the progression of hypoxia was investigated.
Taken together, the in-vitro 3D model of HPC resembles many features of the original tumor. The model can help to develop new treatment approaches for HPC.
Bioengineering of a tumour-stroma 3D-tumouroid co-culture model of hypopharyngeal cancer
Santu Saha
Added on: 07-03-2023
A blueprint for tumor-infiltrating B cells across human cancers
2023
Chinese Academy of Sciences, Shanghai, China(1)
Fudan University, Shanghai, China(2)
Zhejiang University, Hangzhou, China(3)
Fudan University, Shanghai, China(2)
Zhejiang University, Hangzhou, China(3)
Tumor-infiltrating B cells have emerged as important players in cancer immunity and served as predictors of response to immunotherapy. In this study, tumour-infiltrating B cells from 21 different types of cancer were examined using tissue and blood samples from patients, and single-cell transcriptome, B cell receptor repertoire, as well as chromatin accessibility data were compiled. Tumor-associated B cells were found to differentiate into antibody-secreting cells by either an extrafollicular pathway or by a more canonical germinal center pathway. Tumors associated with the extrafollicular B cell profile demonstrated poor clinical prognosis and resistance to immunotherapy compared with tumors harbouring germinal center B cells. Alterations in the availability of glutamine-derived metabolites, which are known to influence T cell–dependent immunosuppression, may be linked to a dysfunctional humoral response and the adverse effect of extrafollicular B cells on tumors.
A blueprint for tumor-infiltrating B cells across human cancers
Xiaoming Zhang(1), Jia Fan(2), Qiang Gao(2), Guoji Guo(3)
Added on: 08-05-2024
NetBID2: computational tool for hidden driver analysis
2023
St. Jude Children’s Research Hospital, Memphis, USA
In this study, the researchers have created an updated method of analysing multi-omic data in an effort to identify hidden drivers of cancer that are not immediately obvious through traditional sequencing approaches. The computational tool, called NetBID2, was designed to find hidden drivers of disease by taking large sets of RNA sequencing data and generating a gene-gene interactome. This interactome allows researchers to track the relationships between driver candidates and their downstream effector genes, thus identifying which signalling proteins are most central to the key relationships that fuel disease. The authors demonstrate the power of NetBID2 using three hidden driver examples in normal tissues and paediatric and adult cancers.
NetBID2 provides comprehensive hidden driver analysis
Jiyang Yu
Added on: 09-14-2023
Obesity treatment restores natural killer cell metabolism in patients
2023
Maynooth University, County Kildare, Ireland
People with obesity (PWO) have functionally defective natural killer (NK) cells, with a decreased capacity to produce cytokines and kill target cells, underpinned by defective cellular metabolism. It is plausible that the changes in peripheral NK cell activity are contributing to the multimorbidity in PWO, which includes an increased risk of cancer. This study investigated whether a 6-month therapy with long-acting glucagon-like peptide-1 (GLP-1) analogues, which are an effective treatment for obesity, could restore NK cell functionality in a cohort of 20 PWO. The data demonstrated that PWO who received GLP-1 therapy have improved NK cell function and cell cytokine production, and that the reported improvements appear to be independent of weight loss.
Glucagon-like peptide-1 therapy in people with obesity restores natural killer cell metabolism and effector function
Andrew E. Hogan
Added on: 06-05-2023
Organoids for rare liver cancer research
2023
Royal Netherlands Academy of Arts and Sciences, Utrecht, Netherlands(1)
The Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands(2)
The Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands(2)
Fibrolamellar carcinoma (FLC) represents a rare type of childhood liver cancer. The aim of this study was to gain molecular understanding of FLC tumorigenesis by using CRISPR-engineered human hepatocyte organoids.
In the developed human hepatocyte organoid models different FLC and FLC-like genetic alterations were introduced to reflect the genetic backgrounds of different cases of FLC. Phenotypic characterizations and comparisons with primary FLC patient tumor samples revealed mutant organoid-tumor similarities. Thus, the engineered human organoid models facilitate the study of FLC.
Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss
Delilah Hendriks(1), Benedetta Artegiani(2)
Added on: 05-08-2023
Organoids of head and neck tumors for treatment optimization and biomarker identification
2023
Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, Netherlands
In this study, organoids were prepared from tumor tissues of HNC patients (head neck cancer, tumors of the head and neck region, characterized by immunohistochemistry and DNA sequencing and a biobank was established. In addition to organoids of the most common HNC tumor type 'squamous cell carcinoma', the biobank also contains organoids of rare tumour types such as salivary gland tumors or intestinal-type adenocarcinoma.
The organoids were exposed to chemotherapy, radiotherapy, and a series of targeted agents. The response of the organoids was compared with the clinical response of the patients. CRISPR-Cas9-based gene editing of organoids was used to validate biomarkers.
Organoids exhibited the DNA alterations found in HNC. A comparison between organoids and patient response to radiotherapy showed that treatment options could be better managed in the adjuvant setting. The radiosensitizing potential of cisplatin and carboplatin was reproduced in the organoids. As in clinical studies, cetuximab showed heterogeneous results and induced radioprotection in most models. Targeted HNC treatments were tested, indicating potential new treatment options that may allow stratification of treatment in the future. In preclinical studies, PIK3CA mutations were identified as biomarkers for response to alpelisib. In clinical trials, however, a more heterogeneous response to treatment with alpelisib was observed. Even organoids with PIK3CA mutations in this study could not predict a response to alpelisib.
Organoids have the potential to serve as a diagnostic tool in personalized medicine for HNC. The response of organoids to radiotherapy (RT) in vitro showed a trend mimicking clinical response, indicating the predictive potential of patient-derived organoids. In addition, organoids could be used for biomarker discovery and validation.
Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification
Hans Clevers, Else Driehuis, Rosemary Millen
Added on: 06-30-2023
Animal-free defined medium for 2D and 3D culturing of normal and cancer cells
2023
Lund University, Lund, Sweden
Cell culturing media often contain animal-derived components, one of the most commonly used is foetal bovine serum (FBS). The safety, batch-to-batch variation, and ethical problems with FBS are acknowledged and therefore worldwide efforts are ongoing to produce FBS-free media. Here, the researchers present the composition of a new defined medium with only human proteins, either recombinant or derived from human tissues. This defined medium supports long-term culturing/routine culturing of normal and cancer cells and can be used for freezing and thawing of cells, i.e. for cell banking. This defined medium provides a leap towards a universal animal product-free cell culture medium.
A new animal product free defined medium for 2D and 3D culturing of normal and cancer cells to study cell proliferation and migration as well as dose response to chemical treatment
Stina Oredsson
Added on: 05-02-2023
Deciphering drug resistance in testicular cancer
2023
University Hospital Bonn, Bonn, Germany
Patients suffering from cisplatin-resistant testicular germ cell tumors are facing poor prognosis demanding novel therapeutic options. In this study, a genome-scale CRISPR/Cas9 activation screen on testicular germ cell tumor cell lines was applied to generate cisplatin-resistant clones. Investigation of candidate genes allowed to identify and describe pathways leading to cisplatin resistance.
Testicular germ cell tumor cell lines were treated with a substance inhibiting neddylation, which is a certain form of post-translational protein modification. This treatment increased cisplatin cytotoxicity and sensitized cisplatin-resistant cells towards cisplatin.
This highlights the potential of neddylation inhibitors in combination with cisplatin as a novel treatment option for testicular germ cell tumors.
Genome-scale CRISPR screen reveals neddylation to contribute to cisplatin resistance of testicular germ cell tumours
Hubert Schorle
Added on: 05-08-2023
Micro-mechanical sensing and imaging of 3D cell culture systems
2023
University of Nottingham, Nottingham, United Kingdom
In this study, a new instrument named ‘OptoRheo’ is described. It combines light sheet fluorescence microscopy with particle tracking microrheology. OptoRheo allows 3D imaging of cells as they proliferate over several days, while simultaneously sensing the mechanical properties of the surrounding extracellular and pericellular matrix at a subcellular scale.
The application of the device was demonstrated by characterizing the extracellular matrix surrounding live breast cancer cells in two distinct culture systems: cell clusters in 3D hydrogels and spheroids in suspension culture.
OptoRheo will allow a better understanding of cell-matrix interactions, the exploration of drug transport through complex cell culture matrices, and the optimization of next-generation of in-vitro disease models.
OptoRheo: Simultaneous in situ micro-mechanical sensing and imaging of live 3D biological systems
Tania Mendonca
Added on: 11-06-2023
Personalized therapeutic strategies for multiple myeloma
2023
ETH Zurich, Zurich, Switzerland
Despite a growing arsenal of approved therapies, multiple myeloma remains incurable and in need of guidelines to identify effective personalized treatments. In this study, ex vivo drug and immunotherapy sensitivities were surveyed across 101 bone marrow samples derived from 70 patients with multiple myeloma.
Multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell investigation were used. To identify the molecular basis associated with differential drug responses, the drug responses were correlated with myeloma protein abundances. Ex vivo drug sensitivity was compared with clinical treatment responses, including to immunotherapy.
Taken together, the study provides molecular insights into diverse treatment strategies for patients with multiple myeloma and enables a personalized medication.
Ex vivo drug response heterogeneity reveals personalized therapeutic strategies for patients with multiple myeloma
Berend Snijder
Added on: 05-05-2023
Photodynamic therapy for glioblastoma in brain organoids
2023
Hospital Clinic de Barcelona—FCRB, Barcelona, Spain(1)
University of Barcelona, Barcelona, Spain(2)
University of Barcelona, Barcelona, Spain(2)
The high recurrence of glioblastoma (GB) that occurs adjacent to the resection cavity within two years of diagnosis urges an improvement of therapies oriented to GB local control. Photodynamic therapy (PDT) has been proposed to cleanse infiltrating tumor cells from parenchyma to ameliorate long-term progression-free survival. The researchers examined 5-aminolevulinic acid (5-ALA)-mediated PDT effects as therapeutical treatment and determined optimal conditions for PDT efficacy without causing phototoxic injury to the normal brain tissue. They used a platform of Glioma Initiation Cells infiltrating cerebral organoids with two different glioblastoma cell lines. The study provides evidence about the effectiveness of PDT to treat high proliferative GB cells in a complex in vitro system, which combines normal and cancer cells and is a useful tool to standardize new strategic therapies.
Preclinical studies with glioblastoma brain organoid co-cultures show efficient 5-ALA photodynamic therapy
Àngels Sierra(1), Ana Sevilla(2)
Added on: 05-02-2023
3D screening model for cervical cancer drugs
2023
Oregon State University, Corvallis, USA
Cervical cancer is the second leading cause of cancer-related death in women under 40 and is one of the few cancers to have an increased incidence rate and decreased survival rate over the last 10 years. However, the development of new anticancer drugs remains a challenge. To facilitate the identification of novel and effective anticancer drugs for cervical cancer, the researchers developed a 3D multilayer multicellular platform of human cervical cancer cell lines and primary human microvascular endothelial cells. The model is suitable for high throughput drug screening methods to evaluate the anti-metastatic and anti-angiogenic drug efficacy simultaneously. Using this platform, the researchers conducted a targeted drug screen of four clinically relevant drugs on two cervical cancer cell lines. Overall, this work provides a valuable platform that can be used to screen large compound libraries for mechanistic studies, drug discovery, and precision oncology for cervical cancer patients.
Engineering high throughput screening platforms of cervical cancer
Kaitlin C. Fogg
Ines A. Cadena et al. Journal of Biomedical Materials Research Part A 2023 [62]
Drug Target Review [63]
Added on: 04-25-2023
Digital spatial profiling of pancreatic cancer
2023
Duke University, Durham, USA
The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. The researchers used digital spatial RNA profiling of dysplastic epithelium from surgically resected IPMN tissues from 12 patients to differentiate subtypes and predict genes associated with malignancy. Gene expression patterns were compared between pancreaticobiliary, intestinal, and gastric foveolar epithelium tumours. This study delineates markers of high-risk IPMN and insights into malignant progression.
Digital spatial profiling of intraductal papillary mucinous neoplasms: Toward a molecular framework for risk stratification
Peter J. Allen
Added on: 05-02-2023
Pan-cancer analysis of transposable elements
2023
Washington University School of Medicine, St. Louis, USA
Cryptic promoters within transposable elements (TEs) can be transcriptionally reactivated in tumors to create new TE-chimeric transcripts, which can produce immunogenic antigens. The researchers performed a comprehensive screen for these TE exaptation events in 33 tumor types, 30 adult tissues and 675 cancer cell lines, and identified 1,068 TE-exapted candidates with the potential to generate shared tumor-specific TE-chimeric antigens (TS-TEAs). The authors highlight tumor-specific membrane proteins transcribed from TE promoters that constitute aberrant epitopes on the extracellular surface of cancer cells. Altogether, they showcase the high pan-cancer prevalence of TS-TEAs and atypical membrane proteins that could potentially be therapeutically exploited and targeted.
Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements
Ting Wang
Added on: 05-02-2023
Organoid models for non-alcoholic fatty liver disease
2023
Hubrecht Institute, Utrecht, Netherlands
The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here, the researchers use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis. Screening of drug candidates revealed compounds effective at resolving steatosis. The researchers present FatTracer, a CRISPR organoid screening platform. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. These organoid models facilitate the study of steatosis aetiology and drug targets.
Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis
Benedetta Artegiani, Delilah Hendriks, Hans Clevers
Added on: 03-15-2023
Genetically engineered human pituitary corticotroph tumor organoids for drug testing
2023
University of Arizona College of Medicine, Tucson, USA
The Cushing's syndrome (CS) is a severe endocrine disorder attributed to an adrenocorticotropic hormone (ACTH)-secreting neuroendocrine pituitary tumor (PitNET), which subsequently leads to chronic hypercortisolism. Following treatment with the selective glucocorticoid receptor (GR) modulator Relacorilant, tumor regression has been reported, but the mechanisms behind this effect remain unknown.
In this study, human pituitary tumor models were generated in the laboratory, either from human stem cells or from tissue obtained from Cushing's syndrome patients. These models were utilized to mimic the development of these tumors. Some of these models exhibited specific genetic alterations typical of these tumors.
Organoids were treated with the GR antagonist Mifepriston or the GR modulator Relacorilant, with or without the somatostatin receptor (SSTR) agonists Pasireotid or Octreotid. Mifepriston led to increased production of a particular receptor called SSTR2 in the tumor cells, along with increased ACTH secretion, which stimulated tumor growth. Relacorilant primarily increased the production of SSTR5 and induced tumor cell death, with minimal ACTH release.
The Hedgehog signalling pathway mediated the induction of SSTR2 and SSTR5 in response to Mifepriston and Relacorilant. Relacorilant sensitized the PitNET organoids to treatment with Pasireotid.
Therefore, the study has highlighted the potential therapeutic benefit of Relacorilant in combination with somatostatin analogues and demonstrated the advantages of Relacorilant over Mifepriston, supporting its further development for the treatment of patients with Cushing's syndrome.
Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators
Yana Zavros
Added on: 09-05-2023
Glyphosate exposure and urinary oxidative stress biomarkers
2023
National Cancer Institute, Bethesda, USA
As there is limited epidemiologic data on one of the most used pesticides worldwide, Glyphosate, and controversial interpreted data in general, this study aims to shed light on the carcinogenic potential. Glyphosate may induce oxidative stress, which is a key characteristic of carcinogens. By analysing certain biomarkers in human urine from farmers who are and were exposed to Glyphosate and Glyphosate-based Herbicides (GBH), oxidative stress can be determined. Urinary glyphosate concentrations were quantified using ion chromatography isotope-dilution tandem mass spectrometry. Biomarkers were quantified using enzyme-linked immunosorbent assays with thiobarbituric acid reactive substances. Those were elevated, supporting the association of exposure to Glyphosate and urinary biomarkers of oxidative stress, which may contribute to development of certain cancers.
Glyphosate exposure and urinary oxidative stress biomarkers in the Agricultural Health Study
Vicky C. Chang
Added on: 08-16-2023
Machine learning method for personalized prediction of brain tumor progression
2023
University of Waterloo, Waterloo, Canada
Glioblastoma multiforme (GBM) is one of the most deadly forms of cancer. Methods of characterizing these tumours are valuable for improving predictions of their progression and response to treatment. A mathematical model called the proliferation-invasion (PI) model has been used extensively in the literature to model the growth of these tumours, though it relies on two key parameters that are difficult to estimate in a patient-specific manner. In this paper, the researchers develop and apply a deep learning model capable of making accurate estimates of these key GBM-characterizing parameters while simultaneously producing a full prediction of the tumour progression curve. The method uses MRI data. The model was applied to a clinical dataset consisting of five patients diagnosed with GBM. For all patients, the researchers derive evidence-based estimates for each of the PI model parameters and predictions for the future progression of the tumour, along with estimates of the parameter uncertainties. This work provides a new, easily generalizable method for the estimation of patient-specific tumour parameters, which can be built upon to aid physicians in designing personalized treatments.
Deep learning characterization of brain tumours with diffusion weighted imaging
Cameron Meaney
Added on: 01-19-2023
In silico mapping of flavonoid compounds for cancer therapies
December 2022
Oswaldo Cruz Foundation (Fiocruz), Eusébio, Brazil
Flavonoids are a class of natural products widely available in medicinal and dietary plants. Their pharmacological use has shown the potential to reduce the risk of different types of cancer, among other prevalent diseases. Their molecular scaffold inhibits the PD-1/PD-L1 axis, an important pathway related to the adaptive immune resistance of cancer cells already targeted for developing new cancer immunotherapy. Here, the researchers aimed to computationally predict the binding mode of flavonoid molecules with PD-1 and/or PD-L1 proteins using unbiased computational methodologies such as blind docking and supervised molecular dynamics simulation. The molecular interactions and dynamics of these predicted poses of protein-flavonoid complexes were further analysed through multiple molecular dynamics simulations. The results introduced unprecedented information on flavonoid interaction and dynamics when complexed with PD-1 checkpoint pathway proteins, and can pave the road for developing new flavonoid derivatives with selective anticancer activity.
In silico mapping of the dynamic interactions and structure-activity relationship of flavonoid compounds against the immune checkpoint programmed-cell death 1 pathway
João Hermínio Martins Da Silva
Added on: 04-25-2023
Bacteria in tumours could influence cancer treatment response
November 2022
Fred Hutchinson Cancer Center, Seattle, USA
Fusobacterium nucleatum (Fn) is a dominant bacterial species in colorectal cancer (CRC) tissue that is associated with cancer progression and poorer patient prognosis. Following a small-molecule inhibitor screen of 1,846 bioactive compounds against an Fn CRC isolate, the researchers found that 15% of inhibitors are antineoplastic agents. Validation of these findings reveals that 5-fluorouracil (5-FU), a first-line CRC chemotherapeutic, is a potent inhibitor of Fn CRC isolates. The researchers also show that CRC E. coli isolates can modify 5-FU and relieve 5-FU toxicity toward otherwise-sensitive Fn and human CRC epithelial cells. Lastly, they demonstrate that ex vivo patient CRC tumour microbiota undergo community disruption after 5-FU exposure and have the potential to deplete 5-FU levels, reducing local drug efficacy. Together, these observations argue for further investigation into the role of the CRC intratumoural microbiota in patient response to chemotherapy.
The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota
Susan Bullman, Christopher D. Johnston
Added on: 01-05-2023
CRISPR/Cas9 for personalized cancer cell therapy
CompanyNovember 2022
PACT Pharma, South San Francisco, USA(1)
University of California, Los Angeles (UCLA), Los Angeles, USA(2)
University of California, Los Angeles (UCLA), Los Angeles, USA(2)
The T cell receptor (TCR) provides the fine specificity of T cells to recognize mutations in cancer cells. Here, the researchers developed a clinical-grade approach based on CRISPR/Cas9 non-viral precision genome editing to simultaneously knock-out two endogenous TCR genes and insert the two chains of a neoantigen-specific TCR (neoTCR), isolated from the patient’s own circulating T cells. Sixteen patients with refractory solid cancers received up to three distinct patient-specific neoTCR-transgenic cell products in a cell first-in-human phase 1 clinical trial. All had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease, and the other 11 had disease progression as the best response on therapy. NeoTCR-transgenic T cells were detected in tumour biopsies post-infusion. This study demonstrates the safety of infusing up to three gene-edited neoTCR T cell products, and the ability of the transgenic T cells to traffic to the patients’ tumours.
Non-viral precision T cell receptor replacement for personalized cell therapy
Stefanie J. Mandl(1), Susan P. Foy(1), Antoni Ribas(2)
Added on: 11-28-2022
Repair processes in the metabolism as drugs targets
November 2022
University of Wuerzburg, Wuerzburg, Germany
Repair enzymes may represent an alternative target class for selective metabolic inhibition, e.g. for cancer treatment, but pharmacological tools to test this concept are still needed.
In this study, it was demonstrated that phosphoglycolate phosphatase (PGP), a repair enzyme in glycolysis, can be targeted with a small molecular compound. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, a compound was identified that inhibits PGP with high selectivity by locking the phosphatase in an inactive conformation. The compound was characterized by biochemical and cellular assays.
This study provides key insights into effective PGP targeting, thereby offering an approach to control glycolysis, and at the same time demonstrates the feasibility of therapeutic approaches to target cellular metabolism.
Glycolytic flux control by drugging phosphoglycolate phosphatase
Antje Gohla
Added on: 11-21-2022
3D bioprinted vascularized breast tumor model
October 2022
Penn State University, University Park, USA
Despite substantial advancements in the development of cancer treatments, the lack of standardized and physiologically-relevant in vitro testing platforms limit the early screening of anticancer agents. A major barrier is the complex interplay between the tumor microenvironment and immune response. To tackle this, a dynamic-flow-based 3D bioprinted multi-scale vascularized breast tumor model, responding to chemo and immunotherapeutics was developed. Heterotypic tumors were precisely bioprinted at pre-defined distances from a perfused vasculature, exhibiting tumor angiogenesis and cancer cell invasion into the perfused vasculature. Bioprinted tumors treated with varying dosages of a chemotherapy medication portrayed a dose-dependent drug response behaviour. Furthermore, a cell-based immune therapy approach was explored, resulting in up to ≈70% reduction in tumor volumes. The presented platform paves the way for a robust, precisely fabricated, and physiologically-relevant tumor model for the future translation of anti-cancer therapies to personalized medicine.
Chemotherapeutics and CAR-T cell-based immunotherapeutics screening on a 3D bioprinted vascularized breast tumor model
Ibrahim T. Ozbolat
Added on: 11-25-2022
3D-fabricated scaffolds for glioma research
October 2022
Delft University of Technology, Delft, Netherlands(1)
Erasmus MC Cancer Institute, Rotterdam, Netherlands(2)
Erasmus MC Cancer Institute, Rotterdam, Netherlands(2)
A major obstacle in glioma research is the lack of in vitro models that can retain the cellular features of glioma cells in vivo. To overcome this limitation, a 3D-engineered scaffold, fabricated by two-photon polymerization, is developed as a cell culture model system to study patient-derived glioma cells. Scanning electron microscopy, (live cell) confocal microscopy and immunohistochemistry are employed to assess the 3D model with respect to scaffold colonization, cellular morphology, and epidermal growth factor receptor localization. Both glioma patient-derived cells and established cell lines successfully colonize the scaffolds. Compared to conventional 2D cell cultures, the 3D-engineered scaffolds more closely resemble in vivo glioma cellular features and allow better monitoring of individual cells, cellular protrusions, and intracellular trafficking. Furthermore, less random cell motility and increased stability of cellular networks are observed for cells cultured on the scaffolds. The 3D-engineered glioma scaffolds, therefore, represent a promising tool for studying brain cancer mechanobiology as well as for drug screening studies.
3D-engineered scaffolds to study microtubes and localization of epidermal growth factor receptor in patient-derived glioma cells
Angelo Accardo(1), Pim J. French(2)
Added on: 12-14-2022
Macrocyclic peptides in drug discovery
October 2022
Technion-Israel Institute of Technology, Haifa, Israel(1)
The University of Tokyo, Tokyo, Japan(2)
The University of Tokyo, Tokyo, Japan(2)
Developing an effective binder for a specific ubiquitin (Ub) chain is a promising approach for modulating various biological processes with potential applications in drug discovery. Here, the researchers combine the Random Non-standard Peptides Integrated Discovery (RaPID) method and chemical protein synthesis to screen an extended library of macrocyclic peptides and to discover a specific binder for this Ub chain. The authors present a powerful strategy for the selective inhibition of protein-protein interactions using cyclic peptides. This study offers an advancement in modulating central Ub pathways and provides opportunities in drug discovery areas associated with Ub signalling.
Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair
Ashraf Brik(1), Hiroaki Suga(2)
Added on: 03-15-2023
Mapped protein structure of Hepatitis C could lead to vaccine
October 2022
The Scripps Research Institute, La Jolla, USA(1)
University of Amsterdam, Amsterdam, Netherlands(2)
University of Amsterdam, Amsterdam, Netherlands(2)
The hepatitis C virus (HCV) causes chronic infection of the liver that can lead to cirrhosis or liver cancer. A prophylactic vaccine could ameliorate these long-term consequences for millions of people, but vaccine development is hampered by the lack of structural information on the vaccine target, a glycoprotein complex located on the surface of the virus. In this study, the researchers determined the cryo-electron microscopy structure of the envelope glycoprotein E1E2 heterodimer in a complex with three broadly neutralizing antibodies. The structure elucidates how the two subunits interact, describes three key neutralizing epitopes, and provides a blueprint for the design of vaccines and drugs that target HCV.
Structure of the hepatitis C virus E1E2 glycoprotein complex
Andrew B. Ward(1), Rogier W. Sanders(2), Kwinten Sliepen(2)
Added on: 11-25-2022
Immunotherapy method to find antigens that trigger specific T cells
2022
Stanford University, Stanford, USA
Adaptive immunity relies on T lymphocytes that use T cell receptors (TCRs) to discriminate among peptides presented by major histocompatibility complex molecules (pMHCs). T-cell recognition of sparse antigenic pMHCs in vivo relies on biomechanical forces. However, in vitro screening methods test potential pMHCs without force and often at high (nonphysiological) pMHC densities and thus fail to predict potent agonists in vivo. Here, the researchers present a technology termed BATTLES (biomechanically assisted T cell triggering for large-scale exogenous-pMHC screening) that uses biomechanical force to initiate T cell triggering for peptides and cells in parallel. BATTLES can be used to explore basic T cell mechanobiology and T cell-based immunotherapies.
A bead-based method for high-throughput mapping of the sequence- and force-dependence of T cell activation
Polly M. Fordyce
Added on: 10-25-2022
A promising anti-tumour drug for ovarian cancer
2022
Cornell University, Ithaca, USA(1)
University of Vienna, Vienna, Austria(2)
University of Vienna, Vienna, Austria(2)
Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Herein, the researchers describe an improved approach to prioritize candidate protein targets based on a combination of dose-dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 distinct dose-dependent targets, despite the broad proteotoxic effects of TRIP. Target-response networks revealed two highly probable targets, of which the Fe−S cluster biogenesis factor NUBP2 was competitively saturated by free TRIP at nanomolar concentrations. Consequently, TRIP emerges as a first-in-class modulator of the scaffold protein NUBP2, which disturbs Fe−S cluster biogenesis at sub-cytotoxic concentrations in ovarian cancer cells.
An anticancer rhenium tricarbonyl targets Fe-S cluster biogenesis in ovarian cancer cells
Justin J. Wilson(1), Samuel M. Meier-Menches(2)
Added on: 03-15-2023
Inhibition of CD39 as a potential strategy for immunotherapy
2022
University of Bonn, Bonn, Germany
An important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. The ectonucleotidases CD39 and CD73 play an essential role in this process. Inhibition of CD39 is thus expected to be an effective strategy for the (immuno)therapy of cancer. However, suitable small-molecule inhibitors for CD39 are not available. Here, the researchers pursued a repurposing approach by screening a self-compiled collection of approved, mostly ATP-competitive protein kinase inhibitors, on human CD39. The best hit compound was further characterized and evaluated in various orthogonal assays and enzyme preparations and on human immune and cancer cells. The tyrosine kinase inhibitor ceritinib, a potent anticancer drug, was found to strongly inhibit CD39 showing selectivity versus other ectonucleotidases. This discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future studies.
Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy
Christa E. Müller
Added on: 10-25-2022
Photo-thermal therapy in a 3D bioprinted glioblastoma model
2022
Sapienza University of Rome, Latina, Italy
Photo-thermal therapy (PTT) is a minimally invasive cancer treatment that relies on the capability of photosensitizing agents to generate highly localized thermal heating for the selective thermal ablation of tumors. This study reports on a powerful combination of 3D bioprinting (3DB) and PTT applications. To this end, the researchers realize a 3DB construct consisting of glioblastoma U87-MG cells in a 3D geometry, incorporating biomimetic keratin-coated gold nanoparticles (Ker-AuNPs) as a photo-thermal agent. The resulting plasmonic 3DB structures exhibit a homogeneous cell distribution throughout the entire volume while promoting the localization of Ker-AuNPs within the cells. Laser-assisted PTT experiments demonstrate the extraordinary ability of Ker-AuNPs to generate heating, producing the highest temperature rise of about 16 °C in less than 2 min.
Biomimetic keratin-coated gold nanoparticles for photo-thermal therapy in a 3D bioprinted glioblastoma tumor model
Luciano De Sio
Added on: 10-25-2022
Immune cell-tumor interaction-on-a-chip
2022
National Research Council, Genoa, Italy
In this study, an organ-on-chip-based approach for recapitulating the immune cell migration and infiltration within a 3D tumor matrix is presented. Human neuroblastoma cells were embedded in a hydrogel matrix and cultured in a compartment physically separated from the fluid flow compartment of the microfluidic device through a porous permeable membrane. Natural killer (NK) cells were isolated from blood of healthy volunteers.
The NK cells were able to migrate into the tumor compartment, and it was demonstrated that their migration is specifically mediated by soluble factors released by the tumor cells. Moreover, the NK cells retained their ability to interact with the tumor cells, and to display a cytotoxic effect resulting in tumor cell apoptosis.
The model represents a promising approach for the screening of the anti-tumor activity of both, drug-based and cell-based therapies. Moreover, it allows the investigation of tumor-immune cell interactions.
A multi-organ-on-chip to recapitulate the infiltration and the cytotoxic activity of circulating NK cells in 3D matrix-based tumor model
Silvia Scaglione
Added on: 10-19-2023
Whole exome sequencing predicts immunotherapy response
2022
New York Genome Center, New York, USA
Immune checkpoint blockade (ICB) has transformed the treatment of metastatic cancer but is hindered by variable response rates. A key unmet need is the identification of biomarkers that predict treatment response. To address this, the researchers analysed six whole exome sequencing cohorts with matched disease outcomes to identify genes and pathways predictive of ICB response. Using this technique, they identify several genes (BCLAF1, KRAS, BRAF, and TP53) and pathways (MAPK signalling, p53 associated, and immunomodulatory) as predictors of ICB response and develop the Cancer Immunotherapy Response CLassifiEr (CIRCLE). Compared to tumor mutational burden alone, CIRCLE led to a superior prediction of ICB response, with a 10.5% increase in sensitivity and an 11% increase in specificity. Such tools may pave the way for better prognostic tools for cancer immunotherapy.
Recurrent somatic mutations as predictors of immunotherapy response
Marcin Imieliński, Neville E. Sanjana
Added on: 10-25-2022
3D printed platform for microgravity research
2022
University of Technology Sydney, Ultimo, Australia
The advancement of microgravity simulators is helping many researchers better understanding the impact of the mechanically unloaded space environment on cellular function and dysfunction. However, performing microgravity experiments on Earth, using simulators such as the Random Positioning Machine, introduces some unique practical challenges, including air bubble formation and leakage of growth medium from tissue culture flask and plates, all of which limit research progress. Here, an easy-to-use hybrid biological platform designed with the precision of 3D printing technologies combined with PDMS microfluidic fabrication processes to facilitate reliable and reproducible microgravity cellular experiments was developed. The system has been characterized for applications in the contest of brain cancer research by exposing glioblastoma and endothelial cells to 24 h of simulated microgravity condition to investigate the triggered mechanosensory pathways involved in cellular adaptation to the new environment. The platform demonstrated compatibility with different biological assays, i.e., proliferation, viability, morphology, protein expression and imaging of molecular structures, showing advantages over the conventional usage of culture flask. The results indicated that both cell types are susceptible when the gravitational vector is disrupted, confirming the impact that microgravity has on both cancer and healthy cells' functionality. In particular, the authors observed deactivation of Yap-1 molecule in glioblastoma cells and the remodelling of VE-Cadherin junctional protein in endothelial cells. The study provides support for the application of the proposed biological platform for advancing space mechanobiology research, also highlighting perspectives and strategies for developing next generation of brain cancer molecular therapies, including targeted drug delivery strategies.
Testing 3D printed biological platform for advancing simulated microgravity and space mechanobiology research
Joshua Chou
Added on: 04-25-2023
Drug-induced phenotypic landscape of colorectal cancer organoids
2022
German Cancer Research Center (DKFZ), Heidelberg, Germany(1)
University Medical Center Mannheim, Mannheim, Germany(2)
University Medical Center Mannheim, Mannheim, Germany(2)
Here, a large-scale image-based phenotyping study of patient-derived cancer organoids was reported to understand underlying factors governing organoid morphology. Colorectal cancer organoids from 11 patients were treated with more than 500 experimental and clinically used small molecules at different concentrations. The morphological heterogeneity of patient-derived organoids and their response to compound perturbations from more than 3,700,000 confocal microscopy images were mapped. The authors found that the resulting landscape of organoid phenotypes was mainly driven by differences in organoid size, viability and cystic vs. solid organoid architecture. Using multi-omics factor analysis for integrating organoid morphology, size, gene expression, somatic mutations and drug activity, biological programs underlying these phenotypes and small molecules that modulate them were identified.
The drug-induced phenotypic landscape of colorectal cancer organoids
Michael Boutros(1), Matthias P. Ebert(2)
Added on: 12-15-2022
In-vitro model of peripheral neuropathies
2022
University of Konstanz, Konstanz, Germany
In vitro models of the human peripheral nervous system (PNS) are required to study chemotherapy-induced peripheral neuropathy (CIPN) and other impairments of the PNS. In this study, induced pluripotent stem cells (iPSCs) were harnessed to generate peripheral sensory neurons enriched in nociceptors and a corresponding protocol was established.
After extensive phenotypic profiling, Ca2+-imaging was chosen as a quantitative endpoint for the assessment of pain-receptor signalling. A case study with the chemotherapeutic drug oxaliplatin at non-cytotoxic concentrations was performed to demonstrate the relevance of the novel PNS model. Neuronal hypersensitivity to otherwise non-activating mechanical stimulation was found that could be blocked by modulators of voltage-gated sodium channels.
These findings indicate that the model is suitable for pharmacological and toxicological studies related to peripheral neuropathies.
Generation of human nociceptor-enriched sensory neurons for the study of pain-related dysfunctions
Marcel Leist
Added on: 09-01-2022
AI identifies characteristic pattern in tumor cells
2022
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Tumors are complex cell tissues that are characterized by high variability, which makes it considerably more difficult to research and identify relevant gene sequences. The present study presents a newly developed algorithm called Icarus, which analyzes differences between cancer cells and the surrounding tissue across different cancer types and data sets. For this purpose, the machine-learning model was fed with numerous data provided to researchers worldwide by various institutions. In the first step, the program created gene signatures and a tumor classifier, through which the algorithm learned to distinguish carcinogenic from healthy cells. Subsequently, the AI was "trained" with various cancer tissue data and the performance of the model was evaluated. Ikarus showed a significantly higher analytical precision than previously developed in silico methods. The model enables not only the characterization of variable, stable cell states but also the functional annotation of individual cells, such as the prediction of differentiation potential, susceptibility to disorders and the prognosis of cell-cell interactions. In all cancer cell types, a characteristic gene sequence pattern has been identified that could provide new insights for cause research. Within this sequence, the algorithm classified certain genes as carcinogenic that have not previously been associated with the development of tumors. The model could prove to be a helpful diagnostic tool and improve therapeutic approaches.
Identifying tumor cells at the single-cell level using machine learning
Altuna Akalin, Verdran Franke
Added on: 08-09-2022
Genetic study identifies therapeutic targets for migraines
2022
Queensland University of Technology (QUT), Brisbane, Australia
Migraine is a common complex disorder with a significant polygenic single-nucleotide polymorphism (SNP) heritability. Here, the researchers utilise genome-wide association study (GWAS) summary statistics to study pleiotropy between blood proteins and migraine under the polygenic model. They collected 4625 publicly available GWAS summary statistics for blood proteins and explored the extent of pleiotropy between migraine and the 325 blood proteins. Pleiotropy analyses link 58 blood proteins to migraine risk at genome-wide, gene and/or single-nucleotide polymorphism levels—suggesting shared genetic influences or causal relationships. The study suggests that Wnt activators that restore Wnt/β-catenin signalling in the brain could represent therapeutic tools against migraine.
Genetic analyses identify pleiotropy and causality for blood proteins and highlight Wnt/β-catenin signalling in migraine
Dale R. Nyholt, Hamzeh M. Tanha
Added on: 11-25-2022
Detecting drug resistance in pancreatic cancer organoids
2022
Technische Universität Dresden, Dresden, Germany
Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. Here the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC) was examined. Resections with tumor-free margins were significantly more frequent when full-dose neoCTx was applied. The authors also assessed if patient-derived organoids (PDOs) can be used to personalize poly-chemotherapy regimens by pharmacotyping of treatment-naïve and post-neoCTx PDAC PDOs. Five out of ten CTx-naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen. Drug testing of CTx-naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly-chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment.
Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment
Daniel E. Stange
Added on: 04-26-2023
Retinal organoid-based model of retinoblastoma
2022
Leibniz Institute DSMZ—German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
In this study, a model for retinoblastoma, a tumor of the eye’s retina that is caused by inactivation of the RB1 tumor suppressor gene, is described. The model is based on organoids derived from the differentiation of human embryonic stem cells into neural retina after the inactivation of RB1 by CRISPR/Cas9 mutagenesis.
Compared to wild-type organoids, loss of RB1 resulted in spatially disorganized organoids and aberrant differentiation, indicated by the disintegration of organoids and depletion of most retinal cell types despite cone photoreceptor cells. The gene expression signature in the model resembled that of tumor material, as revealed by transcriptome analysis.
The organoid-based model enables research on retinoblastoma, understanding of tumor development, and preclinical research.
RB1-negative retinal organoids display proliferation of cone photoreceptors and loss of retinal differentiation
Laura Steenpass
Added on: 08-18-2022
Single-cell mapping identifies cell type–specific genetic control of autoimmune disease
2022
Garvan Institute of Medical Research, Sydney, Australia(1)
University of Tasmania, Hobart, Australia(2)
University of Tasmania, Hobart, Australia(2)
The human immune system displays substantial variation between individuals, leading to differences in susceptibility to autoimmune disease. This work brings together population genetics and single-cell RNA (scRNA)-seq data to uncover drivers of interindividual variation in the immune system. Single-cell RNA sequencing data (scRNA-seq) of peripheral blood mononuclear cells from 982 healthy human volunteers are used for this purpose. The study's results demonstrate how segregating genetic variation influences the expression of genes that encode proteins involved in critical immune regulatory and signalling pathways in a cell type-specific manner. Understanding the genetic underpinnings of immune system regulation will have broad implications in the treatment of autoimmune diseases and infections, transplantation, and cancers.
Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease
Joseph E. Powell(1), Alex W. Hewitt(2)
Added on: 09-13-2022
Patient-derived pancreatic cancer-on-a-chip
2022
Rush University Medical Center, Chicago, USA
This study demonstrates a tumour-chip device engineered to mimic the pancreatic ductal adenocarcinoma (PDAC) tumour microenvironment by incorporating patient-derived organoids and stromal cells, specifically pancreatic stellate cells, and macrophages. Establishing patient-derived organoids in a multicellular microfluidic chip device prolongs cellular function and longevity and successfully establishes a complex organotypic tumour environment that incorporates desmoplastic stroma and immune cells. When primary cancer cells in monoculture were subjected to stroma-depleting agents, there was no effect on cancer cell viability. However, targeting stroma in the developed tumour-chip model resulted in a significant increase in the chemotherapy effect on cancer cells, thus validating the use of this tumour-chip device for drug testing.
Patient-derived pancreatic cancer-on-a-chip recapitulates the tumor microenvironment
Faraz Bishehsari
Added on: 04-28-2022
Patient-specific model for drug-induced cardiotoxicity
2022
University Medical Centre Göttingen, Goettingen, Germany
In this study, a human induced pluripotent stem cell (iPSC)-based model of doxorubicin (DOX)-induced cardiac dysfunction in patients with aggressive B cell lymphoma was developed. It was shown that cells derived from patients that have suffered from cardiac dysfunction are persistently more susceptible to detrimental effects of DOX treatment compared to controls. This included augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. On a patient-specific level, it was demonstrated that control cells upregulated the expression of certain genes in a DOX-dependent manner to avoid cytoplasmic Ca2+ overload and heart failure.
The patient-specific stem cell-based platform of drug-induced cardiotoxicity can be used to unravel the underlying mechanism and to identify associated genetic variants, thereby also providing new targets for the therapy.
Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients
Katrin Streckfuss‑Bömeke
Added on: 08-18-2022
3D printed cancer metastasis model
2022
Wuhan University, Wuhan, China(1)
Zhongnan Hospital of Wuhan University, Wuhan, China(2)
Zhongnan Hospital of Wuhan University, Wuhan, China(2)
To develop a 3D model for cancer invasion, an acoustic bioprinting technology was used to construct tumour microtissues. Cancer-associated fibroblasts (CAFs) derived from a colorectal cancer patient were incorporated into gel droplets and printed into a 3D microtissue. After depositing a tumour organoid derived from the same patient, the 3D bio-printed microtissue was used to model the cancer cell migration and invasion from the tumour organoid into the 3D CAF microtissue. The drug sensitivity of the invasion model was tested using the clinical drug 5-Fluorouracil (5-FU). The invasion phenomenon and drug treatment results were highly consistent with clinical diagnosis and treatment. By using patient-derived cancer samples, the assay holds potential for personalized treatment.
Model cancer metastasis using acoustically bio-printed patient-derived 3D tumor microtissues
Shishang Guo(1), Hang Hu(2)
Added on: 03-17-2022
AI tool predicts who will develop pancreatic cancer based on CT images
2022
Cedars-Sinai Medical Center, Los Angeles, USA
Pancreatic ductal adenocarcinoma (PDAC) is not only the most common form of pancreatic cancer, but it is also the most lethal. However, early-stage diagnosis is challenging because there are no specific diagnostic biomarkers.
This study used electronic medical records from 36 PDAC patients diagnosed with cancer in the past 15 years who underwent CT scans six months to three years before their diagnosis. These CT images were considered normal at the time they were taken.
The AI tool was trained to analyze these prediagnostic CT images and compare them to CT images of 36 people who had not developed cancer. The researchers reported that the model identified, with 86% accuracy, the people who were eventually diagnosed with pancreatic cancer and those who were not.
The AI model detected differences on the surface of the pancreas between people with cancer and healthy controls. These texture differences could be the result of molecular changes that occur when pancreatic cancer develops.
Accordingly, the method could enable early detection of PDAC, giving more people the opportunity to have their tumor completely removed by surgery.
Predicting pancreatic ductal adenocarcinoma using artificial intelligence analysis of pre-diagnostic computed tomography images
Debiao Li
Added on: 05-16-2022
Air-liquid interface exposure
2022
Environmental Health Science and Research Bureau, Ottawa, Canada
An air-liquid interface (ALI) exposure system for reproducible exposure of cells to gases was developed in this study. Optimization of the exposure conditions (temperature, humidity and airflow) resulted in stable and reproducible delivery and reliable monitoring of the test atmospheres for human lung cancer (A549) cells at the ALI. Toxicologically-relevant biological responses were assessed during exposure of cells to air or ozone. The described optimization process is critical to ensure that toxicity can be attributed to the action of the test agent, rather than to suboptimal exposure conditions. This facilitates the development of advanced in vitro-based approaches for inhalation toxicology.
Establishing an air-liquid interface exposure system for exposure of lung cells to gases
Errol Thomson
Added on: 05-27-2022
Bone cancer organoids for drug discovery
2022
University of California, Los Angeles, USA
In this proof-of-concept study, organoids from seven chordoma tumour samples obtained from five patients presenting with tumours in different sites and stages of the rare disease were established. The organoids recapitulated features of the original parent tumours and inter-as well as intrapatient heterogeneity between samples obtained from the same patient at different time points and sites. High-throughput screenings of > 230 drugs were performed and the most effective molecules for the treatment of the respective tumour were identified. The high-throughput screening platform allows testing of hundreds of therapeutic agents, with results available within a week from surgery. It may be used to tailor therapy to each individual patient.
Personalized chordoma organoids for drug discovery studies
Alice Soragni
Added on: 03-25-2022
Chlamydia and HPV co-infection in patient-derived ectocervix organoids
2022
Max Planck Institute for Infection Biology, Berlin, Germany
Coinfections with pathogenic microbes continually confront cervical mucosa, yet their implications in pathogenesis remain unclear. Lack of in vitro models recapitulating cervical epithelium has been a bottleneck to study coinfections. Using patient-derived ectocervical organoids, the researchers systematically modelled individual and coinfection dynamics of Human papillomavirus (HPV)16 and Chlamydia, associated with carcinogenesis. Organoids modelling HPV16 infection develop the characteristics of precancerous lesions while retaining the self-renewal capacity and organise into mature stratified epithelium similar to healthy organoids. HPV16 interferes with Chlamydia development and induces persistence. Strikingly, Chlamydia impedes HPV-induced mechanisms that maintain cellular and genome integrity, including mismatch repair in the stem cells. This study demonstrates the hazard of multiple infections and the unique cellular microenvironment they create, potentially contributing to neoplastic progression.
Modelling Chlamydia and HPV co-infection in patient-derived ectocervix organoids reveals distinct cellular reprogramming
Cindrilla Chumduri
Added on: 11-28-2022
Influence of cancer cell secretion on cardiomyocytes
2022
University Medical Centre Mannheim, Mannheim, Germany
The aim of this study was to investigate the role of cancer cell secretion on cardiac dysfunction including arrhythmias, which appears frequently in patients with cancers. Human-induced pluripotent stem cell-derived cardiomyocytes generated from skin biopsies of three healthy donors were treated with media used for culturing gastrointestinal cancer (AGS and SW480) cells.
qPCR, patch-clamp experiments, western blotting, DNA methylation and demethylation analysis were performed. To prove that the observed changes of ion channel expression induced by cancer cell secretion were related to enhanced DNA methylation, methylation was reduced by overexpression of a demethylating enzyme (TET1). Gastrointestinal cancer cell secretion was shown to influence cardiac ion channel expression and function, which may contribute to the occurrence of arrhythmias in cancer patients.
Investigating the regulatory signalling, especially the epigenetic modifications of ion channels, could provide opportunities for discovering new therapeutic targets for treating arrhythmias in cancer patients.
Regulation of ion channel function in human-induced pluripotent stem cell-derived cardiomyocytes by cancer cell secretion through DNA methylation
Xiaobo Zhou
Added on: 10-27-2022
Investigating of an oncolytic virotherapy using breast cancer organoids
2022
University of Tuebingen, Tuebingen, Germany
An established three-dimensional organoid model derived from the tissue of 10 patients with primary breast cancer was used to develop an experimental protocol for infecting organoid cultures with oncolytic viruses. The oncolytic effects of a measles vaccine virus and a vaccinia virus genetically engineered to express either fluorescent proteins or a suicide gene were investigated. The method demonstrated that all oncolytic viruses significantly inhibited cell viability in organoid cultures derived from breast cancer tissue. The model provides a promising in-vitro method to help further testing and engineering of new generations of virotherapeutic vectors.
A three-dimensional organoid model of primary breast cancer to investigate the effects of oncolytic virotherapy
André Koch
Added on: 04-22-2022
Liquid pearls method for drug testing against pancreatic tumors
Company 2022
Université de Strasbourg, Illkirch, France
In this study, human pancreatic tumor cell lines were used to identify compounds with anticancer activity. So-called liquid pearls were produced, in which human pancreatic chemo-resistant cells were injected. Within the pearls, cancer organoids were formed and challenged with cannabis extracts that were injected directly into the pearls. Different plant extracts were used and corresponding inhibitory concentration (IC50) values were determined, compounds exhibiting anticancer activity were identified, and the mechanism of action for apoptosis induction was studied. The results were compared with those obtained with Gemcitabine, a drug widely used in patients with pancreatic cancers. While gemcitabine only triggers cell cycle arrest, the cannabinoid extract also activates the cell signalling cascade leading to programmed cell death.
The results emphasize the potential of natural products for pancreatic cancer therapy and demonstrate the applicability of liquid pearl technology for drug screening processes.
Cannabis sativa extract induces apoptosis in human pancreatic 3D cancer models: Importance of major antioxidant molecules present therein
Christian D. Muller
Added on: 11-24-2022
Algorithm identifies unknown driver mutations in cancer cells
2022
German Cancer Research Center (DKFZ), Heidelberg, Germany
The development and spread of malignant tumors is associated with the increased occurrence of mutations. In the coding area of the genome, cancer-causing gene segments can already be identified as far as possible. The non-coding area, which includes important regulatory sequences, has so far remained unexplored due to methodological limitations. The distinction between driver mutations and neutral "passenger" mutations is particularly difficult. The present study describes a newly developed algorithm (sigDriver) that detects changes in the genetic material and evaluates them with regard to their cancer driver potential. The research group investigated three characteristic mutation signatures associated with the emergence of hotspots. For this purpose, the genetic material of a total of 3813 tumors was analyzed, whose entire genome had been sequenced as part of the International Cancer Genome Consortium (ICGC), The Cancer Genome Atlas program, as well as in a study on pediatric tumors. The new method follows an automated search-then-annotate approach; i.e. all mutations that the algorithm classified as carcinogenic were analyzed by means of differential expression analysis and annotation. The algorithm unerringly identified all already known hotspots, as well as presumed new drivers in the coding as well as non-coding area and enables a valid differentiation of driver and passenger mutations. The method can help to uncover further, unknown cancer drivers (especially in the regulatory field) in larger patient cohorts with the same type of cancer and is freely available to researchers worldwide.
Association of mutation signature effectuating processes with mutation hotspots in driver genes and non-coding regions
Marc Zapatka, John K. L. Wong
Added on: 08-12-2022
In silico analysis identifies possible COVID-19 cytokine storm drugs
2022
Spanish National Cancer Research Centre, Madrid, Spain
Among the causes of mortality triggered by SARS-CoV-2 infection, the development of an inflammatory “cytokine storm” (CS) plays a determinant role. Here, the researchers used transcriptomic data from the bronchoalveolar lavage fluid (BALF) of COVID-19 patients undergoing a CS to obtain gene signatures associated with this pathology. Using these signatures, they interrogated the Connectivity Map (CMap) dataset that contains the effects of over 5000 small molecules on the transcriptome of human cell lines and looked for molecules whose effects on transcription mimic or oppose those of the CS. As expected, molecules that potentiate immune responses such as PKC activators are predicted to worsen the CS. In addition, the researchers identified the negative regulation of female hormones among pathways potentially aggravating the CS, which helps to understand the gender-related differences in COVID-19 mortality. Regarding drugs potentially counteracting the CS, they identified glucocorticoids as a top hit, which validates their approach as this is the primary treatment for this pathology. Interestingly, the analysis also reveals a potential effect of MEK inhibitors in reverting the COVID-19 CS, which is supported by in vitro data that confirms the anti-inflammatory properties of these compounds.
An in silico analysis identifies drugs potentially modulating the cytokine storm triggered by SARS-CoV-2 infection
Oscar Fernandez-Capetillo
Added on: 03-16-2022
Macrophage anti-tumour response in a microfluidic chip
2022
Radboud University Medical Center, Nijmegen, Netherlands
This study reports a microfluidic tumour-on-a-chip system combining macrophages and tumour cells in a 3D collagen matrix. For proof of concept, the platform was utilized to obtain novel insights for a promising therapeutic combination of an IgA antibody against epidermal growth factor receptor (EGFR) with a CD47-blocking fusion protein acting as an innate immune checkpoint inhibitor. Employing the chip assay, it was shown that the combination of anti-EGFR IgA and a CD47 checkpoint inhibitor synergistically activate macrophage phagocytic function to specifically kill cancer cells. The model is especially useful in immuno-oncology, as there are substantial interspecies differences in how cells of the immune system operate. Thus, the developed model allows a human-centred investigation of novel immunotherapeutic approaches.
Evaluation of immunotherapies improving macrophage anti-tumor response using a microfluidic model
Wouter P.R. Verdurmen
Added on: 04-28-2022
Optical genome mapping as a prognostic tool for myeloid malignancies
2022
Ruhr-University Bochum, Bochum, Germany
Cytogenetic diagnostics play a crucial role in risk stratification and classification of myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), thus influencing treatment decisions. Optical genome mapping (OGM) is a novel whole-genome method for the detection of cytogenetic abnormalities. This study assessed the applicability and practicality of OGM as a diagnostic tool in AML and MDS patients. In total, 27 patients with AML or MDS underwent routine diagnostics as well as OGM following a recently established workflow. Methods were compared regarding concordance and content of information. In 93%, OGM was concordant to classical karyotyping and a total of 61 additional variants in a predefined myeloid gene-set could be detected. In 67% of samples, the karyotype could be redefined by OGM. The method has the potential to enter routine diagnostics as a gold standard for cytogenetic diagnostics. Furthermore, OGM can serve as a tool to identify genetic regions of interest and future research regarding tumor biology.
Optical genome mapping reveals additional prognostic information compared to conventional cytogenetics in AML/MDS patients
Deepak B. Vangala
Added on: 03-10-2022
Organ-on-a-chip model of bone marrow
2022
University of California, Davis, USA
In this study, a novel microfluidic device is presented that is capable of supporting two separate niches of human bone marrow while maintaining physiological proximity and communication. The microtissue model of human bone marrow displayed a perfusable, 3D vascular network and expression of extracellular matrix proteins and other biomarkers that are present in the native bone marrow. Hematopoietic stem/progenitor cells were cultured and maintained in the device for up to two weeks and were able to differentiate into mature neutrophils that could egress from the marrow compartment and into adjacent microfluidic lines. The platform allows for investigation of the stem cell niche and was used to visualize cancer metastasis; thus, it may also be a useful tool for drug discovery or investigation of haematological diseases.
Organ-on-a-chip model of vascularized human bone marrow niches
Steven C. George
Added on: 04-28-2022
Bioprinted neuroblastoma model for drug testing
December 2021
Technische Universität Berlin, Berlin, Germany
A three-dimensional model for neuroblastoma composed of a human neuroblastoma cell line (IMR-32) in a renal environment made of human embryonic kidney cells and primary human kidney fibroblasts is demonstrated. The model was produced using a commercially available bioprinter. In this simplified metastasis model, neuroblastoma cells were surrounded by a microenvironment made up of human kidney cells. Two drugs were exemplarily tested in this model: While one of them selectively killed the cancer cells by apoptosis induction but did not affect the renal cells in the therapeutically effective concentration range, the other induced cell death in both cell types. This cancer model allows the testing of cytotoxicity and tumour selectivity of new anticancer drugs, and the open scaffold design enables the free exchange of tumour and microenvironment by any cell type.
Bioprinted cancer model of neuroblastoma in a renal microenvironment as an efficiently applicable drug testing platform
Jens Kurreck
Added on: 04-22-2022
Hypoxic 3D pancreatic cancer model
December 2021
University College London, London, United Kingdom
In this study, the impact of in vitro hypoxia (5% O2) on the radiotherapy treatment response of pancreatic cancer cells (PANC-1) was investigated in a novel polymer-based macroporous scaffold that was surface modified with proteins for extracellular matrix mimicry.
The results demonstrated an increased post-radiation viability and reduced apoptosis, in hypoxia compared to normoxic cultures, revealing hypoxia-induced radioprotection. The novel platform for radiation treatment screening enables a more accurate preclinical assessment of treatment strategies.
On the evaluation of a novel hypoxic 3D pancreatic cancer model as a tool for radiotherapy treatment screening
Eirini Velliou
Added on: 06-22-2022
Microfluidic system for multi-analyte monitoring of metabolites in 3D cell cultures
December 2021
University of Freiburg, Freiburg, Germany
Three-dimensional cell cultures with patient-derived stem cells are essential in vitro models for more efficient and personalised cancer therapy. Currently, culture conditions and metabolite concentrations, especially hypoxia, in microphysiological systems are often not continuous and accessible in situ. However, understanding and standardizing the cellular microenvironment is key to successful in vitro models. Here, we developed a microfluidic organ-on-chip platform for matrix-based, heterogeneous 3D cultures with fully integrated electrochemical chemosensor and biosensor arrays for the energy metabolites oxygen, lactate, and glucose. Advanced microstructures enable easy cell matrix integration, compartmentalization and microfluidic access. Patient-derived, triple-negative breast cancer stem cells develop into tumor organoids in a heterogeneous spheroid culture on the chip. The system thereby enables on-chip multi-analyte metabolite monitoring under dynamic conditions in a matrix-based culture for more than a week and comprehensive control of culture conditions, including hypoxia, and simultaneous verification by integrated sensors. Responses to changes in culture conditions and exposure to anticancer drugs, such as metabolite consumption and production rates, could be quantitatively recorded in real-time. The approach highlights the importance of continuous in situ metabolite monitoring in 3D cell cultures with respect to standardization and control of culture conditions and drug screening in cancer research. Overall, the results highlight the potential of microsensors in organ-on-chip systems for a successful application, e.g. in personalised medicine.
Microfluidic organ-on-chip system for multi-analyte monitoring of metabolites in 3D cell cultures
Andreas Weltin
Added on: 12-22-2021
Obesity at a young age - a risk factor for early colorectal cancer
December 2021
German Cancer Research Center, Heidelberg, Germany
The incidence of colorectal cancers in young adults is increasing. At the same time, the proportion of overweight and obese young people is also on the rise. Whether there is a connection between these two observations, however, is still unknown. Here, the researchers drew on data from the ongoing DACHS case-control study, one of the world's largest trials of colorectal cancer. 747 cancer patients and 621 healthy controls under the age of 55 were asked about their weight at the ages of 20 and 30 and about 10 years before the cancer diagnosis or the survey, respectively. From the data, the researchers determined the risk of early colorectal cancer in overweight (BMI 25 to <30 kg/m2) and obese (BMI ≥30 kg/m2, obesity) people compared with normal-weight (BMI <25 kg/m2) people. The team found that the risk of early colorectal cancer was about twice as high in obese people as in those of normal weight. If obesity was already present at age 20, their risk was even 2.6 times higher. Overweight people with a BMI of 25 to 30 kg/m2 also had an increased risk of developing colorectal cancer at an early age. These findings support the suggestion that the increase in overweight and obesity in the younger generation is one of the main reasons for the more frequent occurrence of early colorectal cancer.
Associations of body mass index at different ages with early-onset colorectal cancer
Hermann Brenner
Added on: 03-10-2022
tBID can directly trigger cell death
December 2021
University of Cologne, Cologne, Germany
During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, the researchers report that tBID can also mediate mitochondrial permeabilization by itself, resulting in the release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. Importantly, this mechanism is physiologically relevant in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to the lack of active BAX and BAK. These findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.
BCL-2-family protein tBID can act as a BAX-like effector of apoptosis
Ana J Garcia-Saez
Added on: 03-16-2022
3D printed colorectal cancer model
November 2021
Medical University of Plovdiv, Plovdiv, Bulgaria
The aim of this study was to establish an improved preclinical disease model for colorectal cancer, closer resembling in vivo carcinomas, to obtain higher predictive properties, and offer opportunities for individualized therapies.
Therefore, a 3D-printed model was developed using human colorectal adenocarcinoma (Caco-2) cells.
Histological assessment revealed the formation of glandular-like structures which show greater pathomorphological resemblance to tumors than monolayer (2D) cultures do. RNA expression profiles in 3D culture were marked by the upregulation of genes involved in cell adhesion and hypoxia and the downregulation of cell cycle programs.
Testing this 3D experimental platform with three of the most commonly used chemotherapeutics in colorectal cancer treatment revealed increased resistance compared to 2D cell cultures. Moreover, the system was successfully extended to primary colorectal cancer samples derived from 3 patients.
A colorectal cancer 3D bioprinting workflow as a platform for disease modeling and chemotherapeutic screening
Victoria S. Sarafian, Yordan Sbirkov
Added on: 12-12-2022
Largest open-source database for bone marrow cell images developed
November 2021
Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
Every day, cytologists around the world use optical microscopes to analyse and classify samples of bone marrow cells thousands of times. This method to diagnose blood diseases was established more than 150 years ago, but it suffers from being very complex. Here, the researchers developed the largest open-access database on microscopic images of bone marrow cells to date. The database consists of more than 170,000 single-cell images from over 900 patients with various blood diseases. On top of the database, the researchers have developed a neural network that outperforms previous machine learning algorithms for cell classification in terms of accuracy, but also in terms of generalizability. This study is a step toward automated evaluation of bone marrow cell morphology using state-of-the-art image-classification algorithms. The researchers aim to further expand their bone marrow cell database to capture a broader range of findings and to prospectively validate their model. The database and the model are freely available for research and training purposes – to educate professionals or as a reference for further AI-based approaches, e.g. in blood cancer diagnostics.
Highly accurate differentiation of bone marrow cell morphologies using deep neural networks on a large image data set
Carsten Marr
Added on: 05-12-2022
Regulation of estrogen receptor signaling in patient-derived breast cancer cultures
November 2021
University of Helsinki, Helsinki, Finland
Breast cancer is globally the most frequent cancer and the leading cause of women’s death. Two-thirds of breast cancers express the estrogen receptor (ER)-positive phenotype. ER-positive tumors have been almost impossible to grow in culture since ER protein is quickly downregulated in vitro. 400 patient-derived breast epithelial and breast cancer explant cultures were grown in various three-dimensional matrix scaffolds, finding that ER is primarily regulated by matrix stiffness. Compression of the cultures with physical force can turn on ER expression in cultured human breast cells. In addition, tumor stiffness, as indicated by mammographic density, is directly correlated to ER expression in breast cancer patients. These findings reveal a mechanobiological component in breast tissue hormonal signalling and enable the development of novel therapeutic interventions.
Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer
Juha Klefström
Added on: 10-24-2022
Efficacy of individualized therapy in leukemia and lymphoma patients
October 2021
Medical University of Vienna, Vienna, Austria
This study tested a novel personalized medicine approach, termed “single-cell functional precision medicine (scFPM)”. The response to drugs on healthy and malignant cells, isolated from freshly removed tissue from patients with advanced aggressive hematologic cancers was investigated with an in-depth analysis. Consequently, the method facilitates the identification of drugs that show cancer cell-specific efficacy, while plausibly exhibiting a reduction in side effects. The high precision of this platform is achieved with automated high-content microscopy and computerized image analysis, formerly called “pharmacoscopy”. The researchers examined 56 patients' tumor cells of real-time biopsies and directly tested the effects of more than 130 candidate compounds to determine which therapy would be effective in each patient. To test the individual benefit to patients, the response time to therapy was compared with that of their respective prior therapy. 54% of the patients had a significant, at least more than 30% prolonged time of progression-free survival under the scFPM-guided therapy. 21% of all patients even showed a long-term response. The study demonstrates that individual therapy tailoring is feasible and effective in breaking resistance to prior therapies.
Functional precision medicine provides clinical benefit in advanced aggressive hematological cancers and identifies exceptional responders
Philipp B. Staber
Added on: 02-23-2022
Impact of the 3D environment of prostate cancer organoids on treatment success
October 2021
Erasmus University Medical Center, Rotterdam, Netherlands
Organoid-based studies are proving promising results in preclinical in vitro cancer research, including prostate cancer (PCa). However, experimental variability in organoid drug trials makes reproducibility difficult. For example, PCa organoids have been observed to be less affected by cabazitaxel, abiraterone and enzalutamide than corresponding single cells prior to organoid formation. Using live-cell imaging of androgen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilisation, this study therefore investigated the influence of 3D scaffolds, spatial organoid distribution and organoid size on treatment efficacy. Scaffolds delayed AR translocation and tubulin stabilisation, with Matrigel causing more delay than synthetic hydrogel and incomplete tubulin stabilisation. The effect of the drug was further attenuated the more centrally the organoids were located in the scaffold shell. In addition, cells in the core of the organoid showed a delayed treatment effect compared to cells on the periphery of the organoid, highlighting the influence of organoid size. These results indicate that the analysis of organoid responses to drugs needs to be interpreted carefully and requires specialised measurement equipment, taking into account the underlying technical aspects.
Modeling prostate cancer treatment responses in the organoid era: 3D environment impacts drug testing
Wytske M. van Weerden
Added on: 03-01-2022
Pancreatic tumor organoids pave the way for single-cell diagnostics
October 2021
Berlin Institute of Health (BIH)/Charité-Universitätsmedizin Berlin, Berlin, Germany(1)
Medical University of Vienna, Vienna, Austria(2)
Medical University of Vienna, Vienna, Austria(2)
Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished ‘classical’ from ‘basal-like’ tumors with more aggressive clinical behaviour. Here, the researchers derive PDAC organoids from 18 primary tumors and two matched liver metastases, and show that ‘classical’ and ‘basal-like’ cells coexist in individual organoids. By single-cell transcriptome analysis of PDAC organoids and primary PDAC, they identify distinct tumor cell states shared across patients. In an imaging-based drug screen, expression of ‘classical’ subtype genes correlates with better drug response. These results thus uncover a functional hierarchy of PDAC cell states linked to transcriptional tumor subtypes and support the use of PDAC organoids as a clinically relevant model for in vitro studies of tumor heterogeneity.
Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy
Christian Conrad(1), Roland Eils(1), Oliver Strobel(2)
Added on: 05-12-2022
Role of microRNAs in lung cancer
October 2021
Technische Universität Darmstadt, Darmstadt, Germany
Intercellular communication plays an essential role in lung cancer. One essential component in this communication are microRNAs (miRs), whose transport has recently attracted increasing research interest. It is known that most cases of non-small cell lung cancer are associated with an overexpression of the pro-inflammatory lipid mediator prostaglandin E2 (PGE2) which strongly promotes tumour growth. Using human lung tumour tissue, cancer cell lines and spheroid cultures, the researchers were able to demonstrate for the first time in this study that PGE2 significantly increases the exosomal secretion of microRNA miR-574-5p in lung cancer cells. This newly discovered relationship between miR-574-5p and PGE2 opens up new therapeutic possibilities for lung cancer.
Small extracellular vesicle-derived miR-574-5p regulates PGE2-biosynthesis via TLR7/8 in lung cancer
Meike J. Saul
Added on: 02-23-2022
Ultra-sensitive cancer detector from 2D materials
October 2021
Singapore University of Technology and Design, Singapore, Singapore
Changes in lipid composition and structure during cell development can be markers for cell apoptosis or various diseases such as cancer. However, current methods are limited in studying these micro-changes as they require complex probe preparation and cannot be reused, making cell monitoring and detection challenging. Here, the researchers developed a direct current (DC) resistance sensor based on two-dimensional (2D) molybdenum disulfide nanosheets to enable cancer cell-specific detection dependent on micro-changes in the cancer cell membrane. The analysis revealed that previously unconsidered perturbations in the lipid bilayer can cause an increase in resistance. Furthermore, a correlation was observed between the resistance and breast cancer epithelial cell (MCF-7) population, illustrating a cell population-dependent sensitivity of the method. The method has a detection limit that is below the baseline for the current state-of-the-art electrical-based biosensors. This combination of a unique 2D material and electrical resistance framework represents a promising approach for the early detection of cancerous cells and to reduce the risk of post-surgery cancer recurrence.
Ultrasensitive two-dimensional material-based MCF-7 cancer cell sensor driven by perturbation processes
Desmond K. Loke, Natasa Bajalovic
Added on: 05-12-2022
3D models of human pancreatic cancer recapitulate tumour biology
2021
Queen Mary University of London, London, United Kingdom(1)
Shanghai Jiao Tong University School of Medicine, Shanghai, China(2)
Shanghai Jiao Tong University School of Medicine, Shanghai, China(2)
Tailored ex vivo models may be particularly useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), as treatment failure in this tumor type has been attributed to the high content of cancer stem cells (CSCs) and the high density of stromal cells and extracellular matrix (ECM). To date, these features could only be partially reproduced ex vivo using organoid and spheroid cultures. Here, the researchers develop a more comprehensive and customizable ex vivo model of PDAC based on 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumorigenicity. Custom modification of the system can control niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Proteomic analysis of these cultures shows a better recapitulation of the matrisome compared to organoids. In addition, patient-specific in vivo drug responses are better reproduced in the composite cultures than in other models. These results support the use of tunable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.
Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology
Daniela Loessner(1), Alvaro Mata(1), Christopher Heeschen(2)
Added on: 10-20-2021
Biomarkers and potential therapy for COPD discovered in human bronchial epithelial cells
2021
Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
Airway mucus acts as an indispensable protective component of the innate immune response against invading pathogens. However, hypersecretion is the main cause of airway obstruction and airway hyperreactivity that contributes to chronic obstructive pulmonary disease (COPD). MicroRNAs (miRNAs) are frequently dysregulated in the pathogenesis of COPD, but the definitive role of miRNAs in airway mucus hypersecretion is not well understood. In this study, a cell model of mucus hypersecretion was established by treating human bronchial epithelial cells (16HBE) with tumor necrosis factor-α (TNF-α). Cell viability and apoptosis were assessed, and the expression of miRNAs miR-146a-5p and miR-134-5p was tested in 16HBE cells treated with TNF-α.
TNF-α treatment resulted in a significant decrease in cell viability and an increase in cell apoptosis and mucus formation in the cells. Moreover, the expression of miR-134-5p and miR-146a-5p was significantly decreased in the cell model. In contrast, forced expression of miRNAs significantly suppressed TNF-α-induced mucus overproduction via inhibition of corresponding signalling pathways. The results suggest that miRNAs may serve as biomarkers for COPD as well as a therapeutic option for patients with hypersecretion of airway mucus.
Tumor necrosis factor-α promotes airway mucus hypersecretion by repressing miR-146a-5p and miR-134-5p levels in human airway epithelial cells
Dan-Bo Dou
Added on: 03-30-2022
Data tool may uncover novel class of GPCRs
2021
Queen’s University Belfast, Belfast, United Kingdom(1)
University of London, London, United Kingdom(2)
University of London, London, United Kingdom(2)
In this study, the researchers have developed a computer-aided data tool that could uncover a novel class of G protein-coupled receptors (GPCRs) and lead to treatment for a range of illnesses. GPCRs are drug targets in many therapeutic areas such as inflammation, infertility, metabolic and neurological disorders, viral infections and cancer. Currently over a third of drugs act via GPCRs. Recent studies have uncovered the existence of allosteric sites that drugs can bind to and provide several therapeutic benefits. The researchers developed a computer-aided protocol to map allosteric sites in GPCRs with a view to start a rational search for allosteric drugs, presenting the opportunity for new solutions and therapies for a range of diseases. According to the team, the computer modelling tool will predict novel sites of binding for potential drugs that are more selective, leading to more effective drug targeting, increasing therapeutic efficacy and reducing side effects. Specifically, the data tool or protocol will uncover a novel class of compounds – allosteric drugs in GPCRs.
Probe confined dynamic mapping for G protein-coupled receptor allosteric site prediction
Irina G. Tikhonova(1), Peter J. McCormick(2)
Added on: 02-23-2022
New AI method could aid the development of T cell-based cancer therapies
2021
MD Anderson Cancer Center, Houston, USA(1)
University of Texas Southwestern Medical Center, Dallas, USA(2)
University of Texas Southwestern Medical Center, Dallas, USA(2)
In this study, the researchers have developed an artificial intelligence (AI) technique that can identify which cell surface peptides produced by neoantigens are recognized by the immune system. By applying this method, called pMTnet, to human tumour genomics data, the authors discovered that neoantigens were generally more immunogenic than self-antigens, but human endogenous retrovirus E (a special type of self-antigen that is reactivated in kidney cancer) is more immunogenic than neoantigens. They further discovered that patients with more clonally expanded T cells that exhibit better affinity against truncal rather than subclonal neoantigens had a more favourable prognosis and treatment response to immunotherapy in melanoma and lung cancer but not in kidney cancer. Thus, pMTnet could lead to new ways to predict cancer prognosis and potential responsiveness to immunotherapies which may help develop treatments such as cancer vaccines and T-cell based therapies.
Deep learning-based prediction of the T cell receptor–antigen binding specificity
Alexandre Reuben(1), Tao Wang(2)
Added on: 02-23-2022
Kidney organoids reveal pathological mechanisms in kidney cancer
2021
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
The loss of tumour suppressor WT1 is associated with Wilms tumour development, a type of kidney cancer. Thus, there is an urge to produce in vitro models that allow easy access to the investigation of disease mechanisms and therapy development studies. Here, human induced pluripotent stem cells with WT1 knockout were used to generate kidney organoids to model Wilms tumour. The results showed that the lack of WT1 during organoid development led to kidney hyperplasia with a lack of differentiation of certain kidney cells. Moreover, the lack of WT1 blocked progenitor cell maturation, recapitulating transcriptional changes associated with a subgroup of Wilms tumour patients showing ectopic myogenesis. Furthermore, it was found that mutant WT1 cells needed untransformed microenvironments to propagate. Overall, the researchers clarify the role of WT1 in kidney development and tumour suppression and demonstrate the viability of kidney organoids as a model for paediatric cancer.
The tumor suppressor WT1 drives progenitor cell progression and epithelialization to prevent Wilms tumorigenesis in human kidney organoids
Joerg Betschinger
Added on: 11-29-2021
Microfluidic pancreas model for cancer research
2021
Purdue University, West Lafayette, USA
The development of pancreatic cancer is closely related to the pathological differentiation of the acinus cells, for which a mutation of the PTF1a gene is considered to be the cause. To compare healthy and diseased pancreatic tissue in vitro, a microfluidic pancreatic acinus-on-chip (PAC) model is introduced. The precise modelling of the micro-cavities was carried out using a newly developed viscous-fingering technique. Cancer cells with inactivated PTF1a genes were introduced into the model's acinus cell chamber, which had previously been genetically modified in the laboratory so that the antibiotic doxycycline induces reactivation of the genes. Cellular changes, cell-matrix interaction, local invasion and endocrine functions of healthy and gene-induced tissue were compared and evaluated by means of bioinformatic analysis. The researchers were able to observe that the cancer cells transformed back to their healthy state during gene activation. In parallel, an increase in the digestive enzyme trypsinogen was noted. Based on the results of the present study, the research group evaluates the PAC model as a valid method for further research on pancreatic tissue in vitro. Besides the model could be helpful for improved drug development and the development of new gene therapies.
Engineering of a functional pancreatic acinus with reprogrammed cancer cells by induced PTF1a expression
Bumsoo Han
Added on: 08-04-2022
Optogenetic human pancreatic cell line
2021
IMC University of Applied Sciences, Krems, Austria
Augmented Toll-like receptor 4 (TLR4) expression was found in nearly 70% of patients with pancreatic adenocarcinoma, which is correlated with increased tumorigenesis and progression. In this study, the researchers engineered a new light-oxygen-voltage-sensing (LOV) domain-based optogenetic cell line (opto-TLR4 PANC-1) that enables the triggering of certain signalling cascades upon blue light-sensitive homodimerisation of the TLR4-LOV fusion protein. Using this cell line, the researchers performed different phenotypic cell-based assays with 2D and 3D cultures, with the aim of controlling cellular activity with spatial and temporal precision. Light exposure enhanced cell attachment, the formation, and extension of invadopodia, and cell migration in 3D spheroid cultures, but no significant changes in proliferation or viability could be detected. The authors conclude that the opto-TLR4 PANC-1 cell line is an ideal tool for investigating the underlying molecular mechanisms of TLR4, thereby providing strategies for new therapeutic options.
Light-inducible spatio-temporal control of TLR4 and NF-κB-Gluc reporter in human pancreatic cell line
Christoph Wiesner
Added on: 12-16-2022
Vascularized glioblastoma on a chip
2021
University of Technology Sydney, Sydney, Australia
In this study, a 3D vascularized glioblastoma on-a-chip model has been developed by combination of a microfluidic system and 3D bioprinting. Glioblastoma cells and endothelial cells were printed separately into the tissue compartment of the device using distinct hydrogels as bioinks. The tissue compartment was surrounded by a circular vascular channel which was separated from the tissue compartment via a porous membrane. Endothelial cells were seeded into the vascular channel, resulting in a functional blood-brain-barrier. The model was tested under microgravity conditions resulting in a significant cell morphological response.
The glioblastoma-on-a-chip model could represent a meaningful biological tool for research in cancer mechanobiology and preclinical research in brain tumor therapy.
A 3D-bioprinted vascularized glioblastoma-on-a-chip for studying the impact of simulated microgravity as a novel pre-clinical approach in brain tumor therapy
Joshua Chou
Added on: 04-05-2023
A personalised human iPSC model for chemotherapy-induced neurotoxicity
2021
Charité - Universitätsmedizin Berlin, Berlin, Germany
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, potentially irreversible adverse effect of cytotoxic chemotherapy often leading to a reduction or discontinuation of treatment which negatively impacts patients' prognosis. To date, however, neither predictive biomarkers nor preventive treatments for CIPN are available, which is partially due to a lack of suitable experimental models. The authors, therefore, aimed to evaluate whether sensory neurons derived from induced pluripotent stem cells (iPSC-DSN) can serve as a human disease model system for CIPN. Treatment of iPSC-DSN with four neurotoxic drugs led to axonal blebbing and a dose-dependent decline of cell viability in clinically relevant ranges, which was not observed for non-neurotoxic compounds. Comparing sensory neurons derived from two different healthy donors, the authors found preliminary evidence that these cell lines react differentially to neurotoxic drugs as expected from the variable presentation of CIPN in patients. In conclusion, iPSC-DSN are a promising platform to study the pathogenesis of CIPN and to evaluate neuroprotective treatment strategies. In the future, the application of patient-specific iPSC-DSN could open new avenues for personalized medicine with individual risk prediction, choice of chemotherapeutic compounds and preventive treatments.
Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons
Wolfgang Boehmerle
Added on: 10-21-2021
Advancing personalized cancer research with machine learning
2021
The Barcelona Institute of Science and Technology, Barcelona, Spain
Researchers led by ICREA researcher Dr. Núria López-Bigas at IRB Barcelona have developed a tool, based on machine learning methods, that evaluates the potential contribution of all possible mutations in a gene in a given type of tumour to the development and progression of cancer.
The new tool has been integrated into the IntOGen platform, developed by the same group and designed to be used by the scientific and medical community in research projects, and into the Cancer Genome Interpreter, also developed by this group and which is more focused on clinical decision-making by medical oncologists.
BoostDM currently works with the mutational profiles of 28,000 genomes analysed from 66 types of cancer. The scope of BoostDM will grow as a result of the foreseeable increase in publicly accessible cancer genomes.
The tool has already generated 185 models to identify mutations in a specific gene in a given type of cancer. For example, it has produced a model that has identified all the possible mutations in the EGFR gene that trigger tumour development in some lung cancers, and another model for the same gene in cases of glioblastoma.
In silico saturation mutagenesis of cancer genes
Nuria Lopez-Bigas, Abel Gonzalez-Perez, Ferran Muiños
Added on: 10-04-2021
Endothelium-on-chip model for the study of T-cell-induced immune defense
Company 2021
Mimetas BV, Oegstgeest, Netherlands
The present study presents an endothelium-on-chip model for the investigation of T cell dynamics in health and disease. The method enables the immune cells to flow in real-time through a three-dimensional blood vessel cultured from human endothelial cells on a membrane-free, microfluidic chip. In an inflammatory reaction, T lymphocytes undergo a multi-stage process. By signalling substances, the T cells are recruited to the inflamed site in the vessel and stick there. Then they leave the vessels and then infiltrate the tissues. To visualize and investigate this process, the model was "supplied with blood" with various fluorescence-labelled T cells. The addition of the inflammation-mediating cytokine TNFα and certain chemokines, as well as the addition of human skin cancer cells, induced transendothelial migration of immune cells. Furthermore, the researchers found a dependency between migration behaviour and the activation state of the T cells. The results show that the model adequately recapitulates the complex process of lymphocyte migration and allows unhindered extravasation of T cells into the surrounding tissue. Due to the user-friendliness and high throughput of the platform, the method proves promising for a routine assay that can improve research into immune diseases and the development of immunotherapy drugs.
A microfluidic 3D endothelium-on-a-chip model to study transendothelial migration of T cells in health and disease
Lenie J. van den Broek
Added on: 08-29-2022
Human liver organoids to study HBV infection and hepatocellular carcinoma
2021
Erasmus University Medical Center, Rotterdam, Netherlands
The molecular mechanisms driving transformation and tumour formation by hepatitis B virus (HBV) are largely unclear due to the lack of a suitable model system. Here, the researchers propose the use of human liver organoids as a platform to model HBV infection and tumour formation. A primary ex vivo HBV infection model was developed by obtaining liver organoids after infection with HBV or HBV-infected serum. Infected organoids showed HBV-specific markers and produced infectious HBV. This platform enables anti-HBV drug screening and toxicity testing.
In addition, HBV replication was examined in organoids that overexpressed the HBV receptor NTCP. These showed no increased susceptibility to HBV, indicating additional host factors. In addition, organoids with integrated HBV were generated for long-term culture and the study of HBV transcription.
Another part of the study was the generation of HBV-infected liver organoids from non-tumour cirrhotic tissue from liver transplant patients. Transcriptomic analyses revealed an aberrant cancer gene signature that could potentially provide new biomarkers for HCC development and surveillance in HBV-infected patients.
Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma
Tokameh Mahmoudi
Added on: 09-05-2023
Microfluidic chip model for drug development against chemoresistance
2021
Texas A&M University, College Station, USA
The leakage of platelets from the vessels into the microenvironment of tumors is associated with increased proliferation of cancer cells, as well as the formation of metastases and leads to chemoresistance in several types of cancer. The present study presents an ovarian-tumor-microenvironment-chip model (OTME-chip) specifically developed for the recapitulation of platelet extrusion and analysis of tumor-cell interaction. In addition to the tumor cell chamber, the microfluidic model consists of a complex 3D hydrogel chamber that reflects the tumor microenvironment and platelet flow in the vessels. By means of gene editing and RNA sequencing analysis, it was observed that the platelets bind to the circulating tumor surface glycoprotein galectin-3 under vascular shear stress via glycoprotein VI (GPVI), which could promote the growth of the cancer cells. Furthermore, the effect of the antiplatelet aggregation drug Revacept, which has already been successfully tested in phase-1 clinical trials in atherosclerosis and stroke, on platelet-tumor-microenvironment interactions was investigated. The bonds between GPVI and galectin-3 were significantly reduced by treatment. In addition, a decrease in proliferation and invasion of tumor cells into the surrounding microtissue was observed. This suggests that GPVI inhibition can also prevent the consequences of a cancer-causing interaction between the platelets and the tumor protein galectin-3 and could reduce the formation of chemoresistance. Based on the results, the OTME-chip, in combination with gene editing and RNA sequence analysis, proves to be a suitable model for analyzing the interaction of cancer cells with cells of the vascular system, as well as their consequences for the tumor microenvironment. The chip model can also be helpful for the development of (concomitant) cancer drugs.
Human tumor microenvironment chip evaluates the consequences of platelet extravasation and combinatorial antitumor-antiplatelet therapy in ovarian cancer
Abhishek Jain
Added on: 08-22-2022
Personalized sequencing for the noninvasive diagnosis of gliomas
2021
Cancer Centre Amsterdam, Amsterdam, Netherlands(1)
Cancer Research UK Cambridge Institute, Cambridge, United Kingdom(2)
University of Cambridge, Cambridge, United Kingdom(3)
Cancer Research UK Cambridge Institute, Cambridge, United Kingdom(2)
University of Cambridge, Cambridge, United Kingdom(3)
Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy because quantities in body fluids are low. Here, the glioma-derived DNA fraction in cerebrospinal fluid (CSF), plasma, and urine samples from patients was determined, using sequencing of personalized capture panels guided by analysis of matched tumor biopsies. By sequencing cfDNA across thousands of mutations, identified individually in each patient’s tumor, tumor-derived DNA in the majority of CSF, plasma, and urine samples was detected. Further, cfDNA fragment sizes were analysed using whole-genome sequencing, in urine samples from 35 glioma patients, 27 individuals with non-malignant brain disorders, and 26 healthy individuals. cfDNA in the urine of glioma patients was significantly more fragmented compared to urine from patients with non-malignant brain disorders and healthy individuals. Machine learning models integrating fragment length could differentiate urine samples from glioma patients, suggesting possibilities for truly non-invasive cancer detection.
Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients
Florent Mouliere(1), Nitzan Rosenfeld(2), Richard Mair(2), Kevin Brindle(3)
Added on: 10-04-2021
Chip model for research of non-alcoholic fatty liver disease
2021
University of Central Florida, Orlando, USA
The development of non-alcoholic fatty liver disease (NAFDL) is associated with a manifestation of metabolic syndrome and is therefore associated with various metabolic disorders and concomitant diseases (type 2 diabetes, obesity, lipid metabolism disorder, arterial hypertension), which complicate the investigation of causes and effective drug therapy. In 1 in 5 people, relatively harmless fatty liver disease (NAFL) can develop into pathological steatohepatitis (NASH), which is associated with the development of inflammation, fibrosis, liver cancer and liver failure. The present study describes a human adipose-liver-on-a-chip model that enables the modelling and research of NAFLD under different metabolic conditions. By integrating human liver and fat cells into a recirculating, serum-free circulatory medium (two-chamber model), the researchers were able to study the metabolic interactions between the tissues over a period of 14 days. In order to evaluate the interactions between liver and fat cells and their significance for a pathological course, monocultures were analyzed in parallel. Different metabolic conditions (healthy, diabetic, obese and pro-inflammatory with TNF-alpha) were simulated in the model via variation of the circulatory medium. In addition, treatment with the antidiabetic drug metformin was evaluated. The results showed that the liver cells are indirectly damaged by insulin-resistant biomarkers and signalling substances of the fat cells, which are characteristic of pathologically progressive NAFDL. The signal cascades and tissue damage differed depending on the medium and model used. In contrast to monocultures, TNF-α-induced steatosis could also be detected in the two-chamber model. Treatment with metformin was able to reduce NASH at doses above the physiological range in isolated liver cells, but in parallel, it led to increased cytotoxicity and cell death. Based on the results, the adipose-liver-on-chip model shows promise for further investigation of aspects of the contribution of a single factor to NAFLD development, as well as for evaluating the preclinical efficacy of drugs and re-evaluating dosage regimens in humans.
Validation of an adipose-liver human-on-a-chip model of NAFLD for preclinical therapeutic efficacy evaluation
James J. Hickman
Added on: 09-07-2022
Computational model to simulate tumorous cell cycle dependent ion current modulation
2021
Graz University of Technology, Graz, Austria
The A549 cell line, derived from non-small cell lung cancer (NSCLC), is a widely used model for the study of lung cancer and the development of anticancer drugs. In this work, the authors present for the first time an electrophysiological model of the A549 human lung adenocarcinoma cell line. The model accounts for the kinetics of the major ion channels contributing to the total membrane current and the resting membrane potential of the cells. Based on experimental data using the whole-cell patch-clamp technique and an extensive literature review, the kinetics of each channel was modelled using a hidden Markov model, and the number of ion channels represented was estimated by fitting the macroscopic currents to the recorded whole-cell currents. The model was parameterized taking into account the specific ion channel activities of the A549 cells obtained from literature data and includes the major functionally expressed ion channels in the plasma membrane of the A549 cells known to date, and also takes into account the respective voltage and calcium dependencies. This approach now allows, for the first time, the simulation of channel interaction, activation and inhibition and, most importantly, the prediction of membrane potential changes for parts of the cell cycle. The availability of this first A549 in silico model 1.0 provides a deeper understanding of the potential roles and interactions of ion channels in tumor development and progression and may aid in the testing, verification, and validation of research hypotheses in lung cancer electrophysiology.
A549 in-silico 1.0: A first computational model to simulate cell cycle dependent ion current modulation in the human lung adenocarcinoma
Christian Baumgartner, Theresa Rienmüller, Sonja Langthaler
Added on: 07-29-2021
Organ-on-a-chip platforms for analysis of metastasis
2021
Izmir Institute of Technology, Izmir, Turkey
As metastasis is a major obstacle for breast cancer patients, model systems are needed to predict the metastatic potential of cancer cells. Two organ-on-chip platforms were developed for the quantitative assessment of invasion and extravasation towards specific tissues. Lung, liver and breast microenvironments were simulated in the chips using tissue-specific cells embedded in a gel matrix. Different breast cancer cell lines were tested using these two platforms. Both invasion/chemotaxis and extravasation results were in agreement with published clinical data.
On-chip determination of tissue-specific metastatic potential of breast cancer cells
Ozden Yalcin-Ozuysal, Devrim Pesen-Okvur
Added on: 12-06-2022
Patient-derived organoid-based radiosensitivity model
2021
Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
In this study, patient-derived tumor organoids were used to determine the correlation between the irradiation response of individual patient-derived rectal cancer organoids and the results of actual radiotherapy of the included 33 patients. Histology and next-generation sequencing analysis confirmed that patient-derived tumor organoids closely recapitulated original tumors, both pathophysiologically and genetically.
A prediction model was developed based on a machine learning algorithm using clinical and experimental radioresponse data. Radiation responses in patients were positively correlated with those in patient-derived tumor organoids. The machine learning-based prediction model for radiotherapy results was demonstrated to have a prediction accuracy of more than 89%.
A patient-derived organoid-based radiosensitivity model for the prediction of radiation responses in patients with rectal cancer
Ui Sup Shin, Younjoo Kim
Added on: 06-23-2022
A tumor organoid model for studying breast cancer
2021
The Second Hospital of Dalian Medical University, Dalian, China
Malignant pleural effusion (MPE) is a serious medical condition in patients with advanced breast cancer (BC). Here, organoid culture technology was applied to culture preoperative puncture specimens and corresponding tumour cells derived from surgical specimens from early-stage BC patients and tumour cells from pleural effusion from an advanced triple-negative BC patient (TNBC) with MPE to investigate whether in vitro models can predict therapies for clinical patients. The organoids matched the histological features of primary BC and showed negative expression of TNBC biomarkers. A 3D drug screening test in combination with the clinical medication situation of the respective patient was performed. The pleural effusion-derived tumour organoids were sensitive to capecitabine and everolimus as single agent treatments. Sensitivity to capecitabine was consistent with this patient's clinical response to capecitabine and with sequencing results. The study concludes that an effective platform for ex vivo pleural effusion tumour organoids from advanced TNBC patients with MPE could be used to identify treatment options and investigate the clinicopathological characteristics of these patients.
Breast cancer organoids from malignant pleural effusion-derived tumor cells as an individualized medicine platform
Zuowei Zhao
Bo Pan et a. In Vitro Cellular & Developmental Biology - Animal 2021 [172]
Physicians Committee for Responsible Medicine [173]
Added on: 11-05-2021
Big Data and AI to compare in vitro and in vivo tumours
2021
Johns Hopkins University, Baltimore, USA
Failure to adequately characterize cell lines, and understand the differences between in vitro and in vivo biology, can have serious consequences on the translatability of in vitro scientific studies to human clinical trials. This project focuses on MCF-7 cells (Michigan Cancer Foundation-7), a human breast adenocarcinoma cell line that is commonly used for in vitro cancer research. In this study, the key similarities and differences in gene expression networks of MCF-7 cell lines compared to human breast cancer tissues are explored. Two MCF-7 data sets (ARCHS4 including 1032 samples and Gene Expression Omnibus GSE50705 with 88 estradiol-treated MCF-7 samples) and one human breast invasive ductal carcinoma (BRCA) data set (The Cancer Genome Atlas, including 1212 breast tissue samples) are used. Weighted Gene Correlation Network Analysis (WGCNA) and functional annotations of the data show that MCF-7 cells and human breast tissues have only minimal similarity in biological processes, although some fundamental functions, such as cell cycle, are conserved. Scaled connectivity—a network topology metric—also show drastic differences in the behaviour of genes between MCF-7 and BRCA data sets. Finally, canSAR is used to compute ligand-based druggability scores of genes in the data sets, and the results suggest that using MCF-7 to study breast cancer may lead to missing important gene targets.
Similarities and differences in gene expression networks between the breast cancer cell line Michigan Cancer Foundation-7 and invasive human breast cancer tissues
Alexandra Maertens
Added on: 06-30-2021
Choroid-on-chip model for drug saftey testing
2021
Eberhard Karls University Tübingen, Tübingen, Germany
Eye disorders are a common pathology with high prevalence. Furthermore, certain therapies have toxic side effects on ocular tissue. However, there are limitations to studying these interactions due to the lack of physiologically-relevant human in vitro models. Thus, there is an urge to develop models that can recapitulate the physiological features of human ocular tissue. Here, human primary melanocytes, and microvascular endothelial cells combined with human induced pluripotent stem cell-derived retinal pigmented epithelial cells were used to build a human organ-on-a-chip model perfused with peripheral blood mononuclear cells of the choroid layer of the eye to perform toxicity and mechanistic studies of immune therapies against cancer. The results showed that, upon challenge, there was transendothelial infiltration of immune cells into the stromal compartment and a cytokine secretion profile resembling the in vivo environment, meaning that there was immunomodulation. Overall, the researchers develop and validate an organ-on-a-chip model of the choroid ocular layer that recapitulates key immunological features and has the potential to be used in safety assessment experiments for immune-oncology therapies.
Human immunocompetent choroid-on-chip: a novel tool for studying ocular effects of biological drugs
Peter Loskill
Added on: 12-02-2021
Genomic interaction networks to identify key cancer cell line characteristics
2021
Maastricht University, Maastricht, Netherlands
Characterisation of the epigenome and transcriptome is critical for understanding the behaviour of cancer cell lines, not only for a better understanding of cancer-related processes but also for future treatments and cancer drug development. Here, the Cancer Cell Line Encyclopaedia (CCLE) 2019 identified potential candidate genes that characterise lymphoid neoplasm-type cancer cell lines. The current findings show that although B- and T-cell lymphomas are thought to differ, they may share similar genomic alterations. These key alterations are important to study and better understand the development and progression of lymphoid neoplasms.
From multi‑omics integration towards novel genomic interaction networks to identify key cancer cell line characteristics
T. J. M. Kuijpers
Added on: 02-15-2022
Tumor and lymph node on chip for cancer studies
2021
National Technical University of Athens, Athen, Greece
Up to 70% of lung cancer metastases are spread through the lymphatic system. Tumor cells have found ways to escape the immune system and even colonize lymph nodes (LNs), which are responsible for eliminating tumor cells. Nowadays, reactivation of the immune response is the basis for the success of immunotherapy in cancer treatment. Understanding how tumors shape the LN environment and how tumor cells that metastasize to the LN can suppress the local immune response will help identify new biomarkers and potentially targeted therapies that can be combined with existing cancer therapies.
The Tumor-LN-oC project addresses the development and validation of a TRL 5 tumor lymph node chip platform (Tumor-LN-oC) consisting of 3D tissue models and microfluidic chips linking surgically removed human primary tumors and LN tissue from the same lung cancer patient. This allows the study of the interaction of primary tumors with LN for individual patients. Sensitive off-chip proteomics and molecular approaches can be used to characterize soluble signals that neutralize the immune response and allow tumor cells to metastasize to and spread from the LN. This will enable the use of existing drugs or the development of new ones that could reverse this process and inhibit tumor growth and spread.
Tumor-LN-oC is coordinated by the Institute of Communication and Computer Systems from Greece, and there are a total of 11 participating partners from 9 European countries.
Ioanna Zergioti
Added on: 01-31-2022
AI to decode the language of cancer and Alzheimer's disease
2021
University of Cambridge, Cambridge, United Kingdom
Intracellular phase separation of proteins into biomolecular condensates is increasingly recognized as a process with a key role in cellular compartmentalization and regulation. And dysfunction is seen as a trigger for cancer and neurodegenerative diseases such as Alzheimer's disease. To understand how protein sequence determines phase behaviour and to develop an algorithm to predict LLPS-prone sequences(liquid-liquid phase separation), datasets of proteins with different LLPS propensities were created. The DeePhase model showed high performance in both distinguishing LLPS-prone proteins from structured proteins and identifying them within the human proteome. Overall, the results shed light on the physicochemical factors that modulate protein condensation and provide a molecular principles-based platform for predicting protein phase behavior.
Learning the molecular grammar of protein condensates from sequence determinants and embeddings
Tuomas P. J. Knowles
Added on: 04-19-2021
Deep learning predicts early cancer onset
2021
Max-Planck-Institut für Molekulare Genetik, Berlin, Germany
The EMOGI (Explainable Multi-Omics Graph Integration) is a machine learning method to identify cancer genes. Based on human patient data, the deep learning algorithm combines data for mutations, copy number changes, DNA methylation and gene expression with the protein-protein interaction for a more accurate prediction of early molecular signs of cancer than other methods known to date. Genetic alterations, as well as non-genetic causes, drive tumorigenesis and some non-mutated genes interact with known cancer genes. 165 novel cancer genes were proposed by this method. EMOGI may open new possibilities for therapeutic substance identification in personalized precision oncology. The method is not restricted to oncology, it can be used in other complex diseases with genetic and non-genetic biomarkers like metabolic disorders to identify disease patterns.
Integration of multiomics data with graph convolutional networks to identify new cancer genes and their associated molecular mechanisms
Annalisa Marsico
Added on: 04-26-2021
E-Morph Assay detects hormone-like effects
2021
German Federal Institute for Risk Assessment (BfR), Berlin, Germany
Endocrine disruptors (EDs) are hormone-like chemicals that can interfere with the endocrine system and are associated with adverse health effects, such as the increased risk of breast cancer in the case of estrogen-like substances. Using AI-automated image-based screening, the E-Morph Assay can identify EDs with estrogen-like effects by applying a substance to human breast cancer cells and observing which substances loosen the connection between cells in the mammary gland, making it easier for breast cancer cells to spread. This test can be fully automated, allowing many substances to be tested in a short period of time.
The E-Morph Assay also shows potential in the development and testing of pharmaceuticals and may be beneficial for regulatory toxicology and biomedical research.
The E-Morph Assay: Identification and characterization of environmental chemicals with estrogenic activity based on quantitative changes in cell-cell contact organization of breast cancer cells
Michael Oelgeschläger
Marja Kornhuber et al. Environment International 2021 [183]
Physicians Committee for Responsible Medicine [184]
Added on: 03-23-2021
Machine learning method to design better antibody drugs
2021
ETH Zurich, Basel, Switzerland
The researchers have created a machine learning method that supports the optimization phase of antibody drugs, potentially helping to develop more effective therapeutics. The standard antibody optimization approach allows the identification of the best antibody from a group of a few thousand. The researchers are now using machine learning to increase the initial set of antibodies to be tested to several million. They provided the proof-of-concept for their new method using antibody cancer drug Herceptin, which has been on the market for 20 years. After screening more than 70 million antibody DNA sequences, the scientists characterized 55 unique antibody variants, some of which bound better to the target protein and one variant was even better tolerated in the body than Herceptin itself. The scientists are now applying their artificial intelligence method to optimize antibody drugs that are in clinical development.
Optimization of therapeutic antibodies by predicting antigen specificity from antibody sequence via deep learning
Sai T. Reddy
Added on: 10-21-2021
New pathomechanism of HLH identified using patient-derived cells
2021
St Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
Hemophagocytic lymphohistiocytosis (HLH) is a rare, severe genetic disease that causes dramatic, life-threatening inflammation by hyperactivation of the immune cells. The cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions are crucial for the elimination of infected or malignant cells, which is impaired in a group of diseases like HLH. The molecular underlying mechanisms remain largely elusive. Cells from a patient suffering from this disease were analysed, revealing a mutation in the enzyme RhoG. By establishing a human RhoG-knock out cell line, it was shown that the absence of RhoG impairs the exocytosis process, thus defining the molecular pathomechanism and identifyig a yet unreported genetic form of HLH.
RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis
Kaan Boztug
Added on: 05-05-2021
AI-based analysis system for the diagnosis of breast cancer
2021
Charité Universitätsmedizin Berlin and Berlin Institute of Health, Berlin, Germany(1)
Technische Universität Berlin, Berlin, Germany(2)
Technische Universität Berlin, Berlin, Germany(2)
The study describes a new tissue-section analysis system for diagnosing breast cancer based on artificial intelligence (AI). Two developments make this system unique: For the first time, morphological, molecular and histological data are integrated into a single analysis. Secondly, the system provides a clarification of the AI decision process in the form of heatmaps. Pixel by pixel, these heatmaps show which visual information influenced the AI decision process and to what extent, thus enabling doctors to understand and assess the plausibility of the results of the AI analysis. This represents a decisive and essential step forward for the future regular use of AI systems in hospitals.
Morphological and molecular breast cancer profiling through explainable machine learning
Frederick Klauschen(1), Klaus-Robert Müller(2)
Added on: 05-11-2021
Distinction between healthy and leukemic blood stem cells
2021
European Molecular Biology Laboratory (EMBL), Heidelberg, Germany(1)
The Barcelona Institute of Science and Technology, Barcelona, Spain(2)
The Barcelona Institute of Science and Technology, Barcelona, Spain(2)
By using single-cell multi-OMICS approaches, the researchers could distinguish between leukemic stem cells and healthy hematopoietic stem cells obtained from acute myeloid leukemia (AML) patients. This approach enables the identification of cancer-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations.
Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics
Lars M. Steinmetz(1), Lars Velten(2)
Added on: 05-11-2021
Onset and development of neuroblastoma
2021
German Cancer Research Center (DKFZ), Heidelberg, Germany
Neuroblastoma is a childhood cancer of the developing nervous system. The cellular origin of neuroblastoma has not been defined yet. Single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development have been studied in the present work aiming to identify the cell of origin of neuroblastoma. Using single-cell RNA sequencing, transcriptional similarities between human embryonic adrenal glands and neuroblastoma tumors could be identified. In addition, there was a clear link between the differentiation status of the tumor cell population and its associated clinical phenotype. This significantly improves knowledge of neuroblastoma onset and opens opportunities for therapeutic approaches.
Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma
Frank Westermann
Added on: 10-25-2022
Pathological genetic variants in early iPSC-stage
2021
German Cancer Research Center (DKFZ), Heidelberg, Germany(1)
Stanford University School of Medicine, Stanford, USA(2)
Wellcome Trust Genome Campus, Cambridge, United Kingdom(3)
Stanford University School of Medicine, Stanford, USA(2)
Wellcome Trust Genome Campus, Cambridge, United Kingdom(3)
More than 1.300 iPSC (induced pluripotent stem cells) lines from human donors were mapped in order to identify the genetic variants which are linked to common as well as rare diseases. To date, the impact of genetic variants on disease in a pluripotent state was not well characterized. With the mapping of a large number of cell lines, it was possible to identify new gene variants and gene expression patterns. With pathological mutations being trackable in a very early stage of cell differentiation, iPSCs are suitable for biomedical analyses.
Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics
Marc Jan Bonder(1), Craig Smail(2), Oliver Stegle(3)
Added on: 04-27-2021
3D bioprinting of bone marrow structure for hematopoietic and cancer models
2021
Rutgers New Jersey Medical School, Newark, USA
In this study, methylcellulose-alginate hydrogel bioinks were fabricated and the bioink composition was optimized to mimic the gross architecture, availability of oxygen, and rheological characteristics of bone marrow. The material was tested using human mesenchymal stem cells and endothelial cells from healthy human donors as well as human breast cancer cells.
The resulting scaffolds were suitable for long-term cultures and offer a foundation for modification with bioactive factors and tissue-specific components to further enhance bone marrow mimicry. Furthermore, it was shown that the structure could be applied to study breast cancer behaviour in bone marrow. Thus, the material can serve as a model to study the healthy microenvironment of the bone marrow, and to uncover new methods to target elusive cancer cells.
A 3D bioprinted material that recapitulates the perivascular bone marrow structure for sustained hematopoietic and cancer models
Pranela Rameshwar
Added on: 04-28-2022
Cancer cells become fluidized and squeeze through tissue
2021
Leipzig University, Leipzig, Germany
Patient samples of mammary and cervix carcinoma contain areas where cells can move or are immobile. Using 3D cell spheroids composed of cells from cancerous and noncancerous cell lines and single live-cell tracking, the authors show that the cancerous sample is fluidized by active cells moving through the tissue. 3D segmentation of the samples show that the degree of tissue fluidity correlates with elongated cell and nucleus shapes. This correlation links cell shapes to cell motility and bulk mechanical behaviour. The authors find two active states of matter in solid tumours: an amorphous glass-like state with characteristics of 3D cell jamming and a disordered fluid state. Individual cell and nucleus shape may serve as a marker for the metastatic potential to foster personalized cancer treatment.
Cell and nucleus shape as an indicator of tissue fluidity in carcinoma
Josef A. Käs
Added on: 05-11-2021
Cell-based assay identifies new anti cancer drugs
2021
Max Planck Institute of Molecular Physiology, Dortmund, Germany
Cancer immune escape is a common problem in cancer therapy. Cells have developed different strategies to evade immune-cell mediated elimination, for example, the modulation of immune checkpoints. The immunoregulatory enzyme indoleamine‐2,3‐dioxygenase (IDO1) is a protein often responsible for this effect and IDO1-inhibitors are hence a potential target for anti-cancer drug discovery. Yet the screening for IDO1 inhibitors was not that successful. This newly developed assay used human cancer cell lines and the chemical reaction the protein catalyzes to form kynurenine, which is measured. Thus, new IDO1 inhibitors and regulators with a potential clinical application could be identified usingthis high throughput method.
Cell‐based identification of new IDO1 modulator chemotypes
Herbert Waldmann
Added on: 05-03-2021
Investigation of natural killer cells using a tumour-on-a-chip model
2021
University of Wisconsin, Madison, USA
In this study, a microfluidic tumour-on-a-chip platform is used to evaluate how natural killer (NK) cells respond to the tumour-induced, immune cell-suppressive environment. The tumour-on-a-chip model includes a microchamber where breast cancer cells are embedded in a 3D matrix and a lumen lined with endothelial cells and perfused with medium to nourish the cells, mimicking the vasculature present in the tumour. This design allows mimicking nutrient, pH, proliferation, and necrosis gradients across solid tumours. The results demonstrate that the suppressive environment created by the tumour gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumour tolerance. The microfluidic tumour-on-a-chip platform represents a model allowing to investigate tumour microenvironment and interaction with immune cells.
Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion
David J. Beebe, Melissa C. Skala, Jose M. Ayuso
Added on: 05-31-2022
Nephrotoxicity tests with sensor-integrated kidney-on-chip platforms
2021
The Hebrew University of Jerusalem, Jerusalem, Israel
The study describes a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. The model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin disrupt proximal tubule polarity at subtoxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporine and cisplatin toxicity by 1000- to 3-fold, respectively. Retrospective study of 247 patients who were diagnosed with kidney damage receiving cyclosporine or cisplatin in combination with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin showed significant (P < 0.001) improvement of kidney function, as well as a reduction in creatinine and uric acid, markers of kidney damage. These results demonstrate the potential of sensor-integrated kidney-on-chip platforms to elucidate mechanisms of action and rapidly reformulate effective therapeutic solutions, increasing drug safety and reducing the cost of clinical and commercial failures.
Mechanism and reversal of drug-induced nephrotoxicity on a chip
Yaakov Nahmias
Added on: 03-22-2021
Big data analysis pinpoints cancer’s key vulnerabilities
2021
Columbia University Irving Medical Center, New York, USA
A new analysis of almost 10,000 patients found that regardless of cancer´s origin, tumors could be stratified in only 112 subtypes and that within each subtype, the master regulatory proteins that control cancer's transcriptional state were virtually identical, independent of the specific genetic mutations of each patient.
The analysis of thousands of tumors from all types of cancer also found that the key genetic programs necessary for the survival of cancer cells are mechanistically controlled by only 24 master regulatory modules, called MR blocks, each one comprising only a handful of such proteins working together.
Rather than looking for drugs targeting mutated genes associated with increasingly smaller patient subsets, as has been done in the past, these findings suggest that a much larger fraction of patients may respond to novel drug classes designed to target master regulatory proteins.
In the future, it may be possible to disassemble each patient's cancer into its specific MR blocks and treat it with drugs designed to target those blocks, either individually or in combination.
A modular master regulator landscape controls cancer transcriptional identity
Andrea Califano, Mariano J. Alvarez, Cory Abate-Shen
Added on: 02-01-2021
Computational tool differentiates between data from cancer cells and normal cells
2021
The University of Texas MD Anderson Cancer Center, Houston, USA
In an effort to address a major challenge when analysing large single-cell RNA-sequencing datasets, researchers have developed a new computational technique to accurately differentiate between data from cancer cells and the various normal cells found within tumor samples.
The new tool, dubbed CopyKAT (copy number karyotyping of aneuploid tumors), allows to more easily examine the complex data obtained from large single-cell RNA-sequencing experiments, which deliver gene expression data from many thousands of individual cells.
CopyKAT uses that gene expression data to look for aneuploidy, or the presence of abnormal chromosome numbers, which is common in most cancers. The tool also helps identify distinct subpopulations, or clones, within the cancer cells.
By applying this tool to several datasets, the authors showed that with about 99% accuracy, the tool could unambiguously identify tumor cells versus the other immune or stromal cells present in a mixed sample.
The team first benchmarked its tool by comparing results to whole-genome sequencing data, which showed high accuracy in predicting copy number changes. In three additional datasets from pancreatic cancer, triple-negative breast cancer and anaplastic thyroid cancer, the researchers showed that CopyKAT was accurate in distinguishing between tumor cells and normal cells in mixed samples.
Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes
Nicholas E. Navin
Added on: 02-11-2021
Detailed tumour profiling
2021
University Hospital Zurich, Zurich, Switzerland
The “Tumor Profiler” project aims to derive the comprehensive molecular profile of tumours in cancer patients and has the potential to predict the efficacy of multiple new cancer medications. This study analyses melanoma, ovarian carcinoma, and acute myeloid leukemia tumors. In addition to the emerging standard diagnostic approaches of targeted NGS panel sequencing and digital pathology, the authors perform extensive characterization using the following exploratory technologies: single-cell genomics and transcriptomics, proteotyping, mass cytometry (CyTOF), imaging CyTOF, pharmacoscopy, and 4i drug response profiling (4i DRP). The authors outline the aims of the Tumor Profiler study and present preliminary results on the feasibility of using these technologies in clinical practice showcasing the power of an integrative multi-modal and functional approaches for understanding a tumor’s underlying biology and for clinical decision support.
The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support
Mitchell P. Levesque
Added on: 01-29-2021
Methylome profile of leukemia already present in the precancerous stage
2021
Dana-Farber Cancer Institute, Boston, USA(1)
Max Planck Institute for Molecular Genetics, Berlin, Germany(2)
Max Planck Institute for Molecular Genetics, Berlin, Germany(2)
The study analyses DNA methylation data from a large cohort of patients with monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL) and shows that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes. The results indicate an early role for this aberrant methylome landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism.
Preneoplastic alterations define CLL DNA methylome and persist through disease progression and therapy
Catherine J. Wu(1), Alexander Meissner(2)
Added on: 02-11-2021
Organ-on-a-chip platform for cell migration, invasion and chemotaxis
2021
Izmir Institute of Technology, Izmir, Turkey
Custom-designed 3D cell-on-a-chip devices are used for the investigation of cellular migration/invasion (IC-chip) and chemotaxis (DDI-chip). The systems reveal human breast cancer cells and macrophages in a paracrine-juxtacrine loop. Comparative 3D co-culture experiments showed that breast cancer cells changed their multicellular organization in the presence of macrophages.
Breast cancer cells and macrophages in a paracrine-juxtacrine loop
Devrim Pesen-Okvur
Added on: 12-21-2022
Prolonged binding results in higher drug efficacy
2021
Goethe University Frankfurt, Frankfurt, Germany
There is increasing evidence that the efficacy of a drug correlates with the residence time of a pharmaceutical substance at its specific binding site. The signalling protein FAK (Focal Adhesion Kinase) plays a role in cancer and inhibition of this kinase induces slowing down breast cancer cells, thus also slowing metastasizing. Analysis of different FAK inhibitors showed that the most effective ones show prolonged residence time at the FAK signalling protein binding site. The binding of effective inhibitors induces a conformational change which explains the prolonged binding. The binding behaviour of the inhibitors can be modelled in computer simulations. The combination of biochemical and molecular biological as well as in silico analyses is a new and promising method for optimizing pharmaceutical active ingredients in the future.
Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2
Stefan Knapp
Added on: 03-11-2022
Single-cell test of cancer drugs
2021
University of Chinese Academy of Sciences, Beijing, China
The researchers paired a powerful algorithm with Raman spectroscopy, which involves using a laser to excite photons in a sample to reveal structural information, including interactions. They examined how rapamycin, an anti-cancer drug, changed the metabolic activity in a human cancer cell line and in yeast. The method is able to rapidly and precisely track and distinguish changes in lipid and protein metabolic-inhibitory effect of rapamycin. The method takes just days compared to traditional tests that can take much longer to see if an individual patient's cells will respond favourably to a drug. It is also very precise, as it can distinguish cancer cell responses to drugs at the single-cell and single-organelle resolution, which is crucial for understanding why the drug is - or is not – effective.
D2O-probed Raman microspectroscopy distinguishes the metabolic dynamics of macromolecules in organellar anticancer drug response
Jian Xu, Maryam Hekmatara
Added on: 01-29-2021
Artificial intelligence study to map risks of ovarian cancer
2021
University of South Australia, Adelaide, Australia
Ovarian cancer is usually diagnosed very late because symptoms are vague and few causes are known. A new project from the University of South Australia will map health data from 273,000 women in the UK Biobank database over the next 4 years to determine genetic, dietary, and physical risks of ovarian cancer.
The machine learning model, which automatically analyzes the data to identify risk patterns, will predict which women will develop ovarian cancer in the next 15 years.
The focus will be on metabolomics, as the scientists involved believe that changes in lipid metabolism are biomarkers for ovarian cancer. Hormonal data and biomarkers in the blood will also be examined to better predict risk.
This project could help diagnose ovarian cancer earlier, improving survival rates.
Elina Hyppönen
Added on: 07-29-2021
Cells programmed for diagnostics and therapy
December 2020
ETH Zurich, Basel, Switzerland
The biological origins of diseases are often highly complex and individual, while the disease itself is often treated with one or a few drugs. Here genetic cassettes were used in order to modify the properties of human cells for future applications in a way similar to the programming of a computer. These engineered cells could then diagnose or even directly treat pathologically altered cells before they trigger a disease. A possible application would be cancer therapy, where these diagnostic, programmed cells can detect certain biochemical cell structures, classified as "cancer cells", and eliminate them directly.
Multiple alternative promoters and alternative splicing enable universal transcription-based logic computation in mammalian cells
Yaakov Benenson
Added on: 04-30-2021
Detection of hidden tumors by imaging and machine learning
December 2020
National Cancer Center, Kashiwa, Japan
The diagnosis of gastrointestinal stromal tumor (GIST) using conventional endoscopy is difficult because submucosal tumor lesions like GIST are covered by a mucosal layer and thus can be overseen. To overcome this issue, near-infrared hyperspectral imaging (NIR-HSI) was combined with machine learning. 12 gastric GIST lesions were surgically resected and imaged ex vivo with a near-infrared (NIR) hyperspectral camera. The site of the GIST was defined by a pathologist using the NIR image to prepare training data for normal and GIST regions. A machine learning algorithm was then used to predict normal and GIST regions. Accuracy was around 86%, therefore NIR-HSI analysis may have the potential to distinguish deep lesions. An endoscope is planned in order to use the method in vivo during standard endoscopy.
Distinction of surgically resected gastrointestinal stromal tumor by near-infrared hyperspectral imaging
Toshihiro Takamatsu
Added on: 02-09-2021
Discovery of substances to combat cancer drug resistance
December 2020
Martin Luther University Halle-Wittenberg, Halle, Germany
Multidrug resistance (MDR) is a widely known problem despite targeted cancer therapies and most patients who experience metastasic cancers die from MDR. The multidrug resistance proteins (MRP) are membrane pumps that pump the anticancer drug out of the cancer cells, thus making them resistant to medications. With the help of different human carcinoma cell lines, a new class of MRP inhibitors was developed which inactivates the pumps so the drug remains in the cancer cell. The findings offer potential new treatments of anticancer drug resistance.
Discovery of novel symmetrical 1,4-dihydropyridines as inhibitors of multidrug-resistant protein (MRP4) efflux pump for anticancer therapy
Andreas Hilgeroth
Added on: 04-30-2021
Improved genome editing by genetic SD-card
December 2020
Pavlov University, St. Petersburg, Russia
A polymer carrier jointly developed by Russian and Belgian researchers can be loaded with genetic material of different types and sizes, which then is delivered into organs and tissues. This provides possibilities for the general development of non-viral carrier systems as well as for targeted tumor therapy. Regarding the latter, the aim is to use the genetic material on the carrier to eliminate genetic defects and thus cure cancer patients. Proof of efficacy and successful transfer was demonstrated using mesenchymal stem cells obtained from patients at the Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation.
Layer‐by‐layer‐assembled capsule size affects the efficiency of packaging and delivery of different genetic cargo
Kirill V. Lepik, Alexander S. Timin
Added on: 02-09-2021
Anti-cancer small-molecule polymerization
November 2020
Broad Institute of MIT and Harvard, Cambridge, USA(1)
Harvard Medical School, Boston, USA(2)
Harvard Medical School, Boston, USA(2)
Using human cells, the study demonstrates that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of B cell lymphoma 6 (BCL6) leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology.
Small-molecule-induced polymerization triggers degradation of BCL6
Benjamin L. Ebert(1), Eric S. Fischer(2)
Added on: 01-29-2021
New therapeutic approach for bone marrow diseases
November 2020
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
Mutations of calreticulin (CALR) are one of the main disease drivers of myeloproliferative neoplasms (MPN), a group of malignant diseases of the bone marrow. In-silico-docking studies, i.e. computer-assisted simulation of the disease mechanism, identified a group of chemicals that block a crucial interaction. It was shown in a cell model that hematoxylin, the most potent of the tested compounds, acts as a novel CALR inhibitor. Mutated CALR cells are selectively killed by using this drug. Thus, a decisive step towards the therapy of this type of blood cancer has been achieved and patients with primary myelofibrosis (PMF), who often develop myeloid leukaemia, could greatly benefit from it.
Hematoxylin binds to mutant calreticulin and disrupts its abnormal interaction with thrombopoietin receptor
Robert Kralovics
Added on: 12-18-2020
Comparison of different liver models using RNA sequencing
October 2020
Maastricht University, Maastricht, Netherlands
In this study, RNA-sequencing (RNA-Seq) was used to analyse the following human in vitro liver cell models in comparison to healthy human liver tissue: cancer-derived cell lines, induced pluripotent stem cell-derived hepatocyte-like cells, human precision-cut liver slices, primary human hepatocytes and 3D liver microtissues. Baseline expression profile and gene regulatory networks were analysed and more comprehensive analyses using non-differentially expressed genes and differential transcript usage were applied. It was shown that 3D liver microtissues exhibited the highest similarity with in vivo liver at the beginning of the incubation period followed by a decrease during long-term incubation. Primary human hepatocytes also showed a high degree of similarity with human liver tissue and allowed stable conditions for a cultivation period of 24 h.
Comparing in vitro human liver models to in vivo human liver using RNA‑Seq
Florian Caiment
Added on: 05-31-2022
Killing cancer naturally
October 2020
Tokyo University of Science, Chiba, Japan
The authors have uncovered a method of combining natural organic compounds which can create anticancer drugs with minimal side effects. The efficiency of the anticancer compounds was tested in human leukemia and lung cancer cells.
Synthesis and cytotoxic evaluation of N-Alkyl-2-halophenazin-1-ones
Kouji Kuramochi
Added on: 12-17-2020
Light controlled cell‐cycle arrest and apoptosis
October 2020
Ludwig-Maximilians-Universität, Munich, Germany
Cell‐cycle interference by small molecules has widely been used to study fundamental biological mechanisms and to treat a great variety of diseases, most notably cancer. The study reports on a photocaging strategy to reversibly arrest the cell cycle at metaphase or induce apoptosis using blue light irradiation. This visible‐light responsive tool can be of great value for biological as well as medicinal approaches in need of high‐precision targeting of the proteasome and thereby the cell cycle and apoptosis.
Light controlled cell‐cycle arrest and apoptosis
Esther Zanin
Added on: 11-06-2020
New cancer diagnostics: A glimpse into the tumor in 3D
October 2020
TU Wien, Vienna, Austria
The authors describe a novel approach that allows pathologists to three-dimensionally analyse malignant tissues, including the tumour-host tissue interface. The visualization technique utilizes a combination of ultrafast chemical tissue clearing and light-sheet microscopy to obtain virtual slices and 3D reconstructions of up to multiple centimetre-sized tumour resectates. Since the imaging of several thousands of optical sections is a fast process, it is possible to analyse a larger part of the tumour than by mechanical slicing. As this also adds further information about the 3D structure of malignancies, the technology will probably become a valuable addition for histological diagnosis in clinical pathology.
3D histopathology of human tumours by fast clearing and ultramicroscopy
Hans-Ulrich Dodt, Inna Sabdyusheva Litschauer
Added on: 11-06-2020
Tumor diagnostics with a combination of machine learning and biochip
October 2020
University of California Irvine, Irvine, USA
Performing single-cell analysis is essential to identify and classify cancer cell types and study cellular heterogeneity. This study combines powerful machine learning techniques with easily accessible inkjet printing and microfluidics technology and integrates a nanoparticle-printed biochip for single-cell analysis. The biochip is simple to prototype, miniaturized and cost-effective, potentially capable of differentiating between a variety of cell types in a label-free manner. Feature classifiers are established and their performance metrics are evaluated. The biochip’s ability to discriminate noncancerous cells from cancerous cells at the single-cell level and to classify cancer sub-type cells is demonstrated. It is envisioned that such a chip has potential applications in single-cell studies, tumour heterogeneity studies, and perhaps in point-of-care cancer diagnostics.
A machine learning-assisted nanoparticle-printed biochip for real-time single cancer cell analysis
Rahim Esfandyarpour
Added on: 11-11-2020
Testing of anti-cancer drugs using a Lab-on-a-chip platform
2020
Izmir Institute of Technology, Izmir, Turkey
Organ-on-a-chip or Lab-on-a-chip devices combined with human 3D cell models are promising tools for human-relevant drug screening. Three different cell models (breast cancer cells, normal mammary epithelial cells and macrophages) were grown on a Lab-on-a-chip platform emulating the cancer microenvironment. The established anti-cancer drug DOX and the new drug candidate KLA were tested using this system. Both drugs were effective on breast cancer cells, while DOX showed higher cytotoxicity and was not selective between breast cancer cells and normal mammary epithelial cells. This platform is a promising tool for the assessment of drug toxicity at the preclinical stage.
A new drug testing platform based on 3D tri-culture in lab-on-a-chip devices
Devrim Pesen-Okvur
Added on: 12-06-2022
Artificial intelligence algorithm for prostate cancer diagnosis in core needle biopsies
Regulatory accepted 2020
UPMC Cancer Pavilion, Pittsburgh, USA
An artificial intelligence (AI) algorithm could successfully diagnose prostate cancer in stained digitized slides of core needle biopsies in a clinical study. The algorithm was able to accurately assess both the stage of the disease and clinically relevant findings, such as perineural invasion. It is already routinely used in the clinic.
An artificial intelligence algorithm for prostate cancer diagnosis in whole slide images of core needle biopsies: a blinded clinical validation and deployment study
Liron Pantanowitz
Added on: 09-25-2020
New method to fight cancer with molecular fibers
2020
Max Planck Institute for Polymer Research, Mainz, Germany
The study describes a modular protein polymerization platform that can form fibrillar intracellular structures, triggering apoptosis. The chemical properties of the system allow polymerization only in the presence of a highly acidic intracellular environment and a high metabolic rate, that are typical for cancer but not for healthy cells. Thus, this platform can potentially be used in advancing new cancer therapies.
Controlled supramolecular assembly inside living cells by sequential multistaged chemical reactions
Tanja Weil, David Y. W. Ng
Added on: 09-16-2020
Breast cancer database to develop personalised treatments
2020
Medical University of South Carolina, Charleston, USA
A new database of 40 breast cancer lines, developed by the Medical University of South Carolina investigators, will help researchers deepen their understanding of these cell lines and speed the development of new gene-targeted therapies. The SUM Breast Cancer Cell Line Knowledge Base, or SLKBase, provides easily navigable genomic, proteomic and other "omic" information on a total of 40 SUM and other patient-derived cell lines.
Development and implementation of the SUM breast cancer cell line functional genomics knowledge base
Stephen P. Ethier
Added on: 09-23-2020
Differences in 2D- and 3D-cancer cell cultures
2020
University of Westminster, London, United Kingdom
This study compared static 2D-cancer cell cultures to 3D- cancer cell cultures, comprising a central mass of breast cancer cells surrounded by collagen type-1 and incorporated fluid flow and pressure. The 3D-cancer model differs by its improved tumour-microenvironment. This includes an extracellular matrix as well as capillary fluid flow and interstitial fluid pressure. The cell lines MDA-MB231 and SKBR3 were employed for this study. The 3D model showed reduced sensitivity to the chemotherapeutic agent Doxorubicin and an overall more aggressive phenotype (furthermore important: downregulation of Ki67 and cadherin-11, upregulation of snail and MMP14, i.a.).
Cancer cells grown in 3D under fluid flow exhibit an aggressive phenotype and reduced responsiveness to the anti‑cancer treatment doxorubicin
Miriam V. Dwek
Added on: 11-26-2020
Human primary cells used to generate organoid models of appendiceal and colorectal cancer
2020
Wake Forest School of Medicine, Winston-Salem, USA
Conducting prospective randomized clinical trials for the treatment of peritoneal malignancies has been historically challenging. Growing evidence support the use of patient-derived tumor organoids (PTO) as a therapeutic response prediction platform. In the present study, the researchers aimed at reconstructing appendiceal and colorectal cancer patient’s tumor in the forms of patient-specific organoids. Tumor tissues were obtained from biopsies of 23 patients, dissociated and the obtained cells were processed to form organoids in vitro. The organoids were then subject to hyperthermic intraperitoneal chemotherapy (HIPEC, the standard of care for these types of cancer) perfusion regimens with varying drug types, drug doses, and temperatures. The capacity of the tested treatment regimens to kill the patient-specific organoid was assessed in vitro using cell viability assays. The model indeed showed a variety of relevant responses depending on the treatment conditions. The study shows proof of principle for utilizing patient-derived organoids as a platform to identify the most efficacious intraperitoneal chemotherapy perfusion protocol in a personalized approach.
Personalized identification of optimal HIPEC perfusion protocol in patient-derived tumor organoid platform
Konstantinos I. Votanopoulos
Added on: 12-21-2021
Microfluidics for dynamic drug testing
2020
University of Twente, Enschede, Netherlands
The authors present a microfluidic device to expose cancer cells to a dynamic, in vivo-like concentration profile of a drug and quantify its efficacy on-chip. In conventional cell culture experiments drug efficacy is tested under static concentrations, whereas in vivo drug concentration follows a pharmacokinetic profile with an initial peak and a decline over time. With the rise of microfluidic cell culture models, including organs-on-chips, there are opportunities to more realistically mimic in vivo-like concentrations. In this study, the microfluidic device contains a cell culture chamber and a drug-dosing channel separated by a transparent membrane, to allow for shear stress-free drug exposure and label-free growth quantification. Dynamic drug concentration profiles in the cell culture chamber were controlled by continuously keeping controlled concentrations of the drug in the dosing channel. The control over drug concentrations in the cell culture chambers was validated with fluorescence experiments and numerical simulations. Exposure of HCT116 colorectal cancer cells to static concentrations of the clinically used drug oxaliplatin resulted in a sensible dose-effect curve. Dynamic, in vivo-like drug exposure also led to statistically significant lower growth compared to untreated control. Continuous exposure to the average concentration of the in vivo-like exposure seems more effective than exposure to the peak concentration only. This microfluidic system will improve efficacy prediction of in vitro models, including organs-on-chips, and may lead to future clinical optimization of drug administration schedules.
Controlled pharmacokinetic anti-cancer drug concentration profiles lead to growth inhibition of colorectal cancer cells in a microfluidic device
Job Komen
Added on: 01-27-2021
Physical activity and advanced cancer
2020
Friedrich‐Alexander‐University Erlangen‐Nürnberg, Erlangen, Germany
The serum of patients with advanced prostate or colon cancer was examined after twelve weeks of whole-body electromyostimulation training. The study found that the serum of these patients inhibited the proliferation of cancer cells and increased their apoptosis. Furthermore, exercise-sensitive genes in prostate cancer cells were identified that may be involved in the exercise-mediated regulation of malignant cell growth and apoptosis.
The study concludes that appropriate physical activity should be part of multimodal cancer therapy.
Physical activity and advanced cancer: evidence of exercise‐sensitive genes regulating prostate cancer cell proliferation and apoptosis
Yurdagül Zopf
Added on: 10-02-2020
Single-molecule imaging to study molecules in live cells
2020
New York University School of Medicine, New York, USA(1)
Université de Montréal, Montreal, Canada(2)
Université de Montréal, Montreal, Canada(2)
Single-molecule imaging, an advanced microscopy technique, allows tracking the movements of tagged individual enzymes by immunofluorescence, thus enabling activity studies at a molecular level. The researchers showed that the telomerase continuously probes the telomeres. It was previously unclear how telomerase molecules are directed to the telomeres within the crowded nucleus. Mutations of a telomeric regulatory factor altered the activity, which contributes to the development of tumours. Thus, an important component of cancer development and ageing could be deciphered.
Single-molecule imaging of telomerase RNA reveals a recruitment-retention model for telomere elongation
Agnel Sfeir(1), Pascal Chartrand(2)
Added on: 06-24-2020
Mechanism of chemotherapeutic drug resistance under cellular stress
2020
Leibniz-Institut für Analytische Wissenschaften ISAS e.V., Dortmund, Germany(1)
Universität Regensburg, Regensburg, Germany(2)
University of Vienna, Vienna, Austria(3)
Universität Regensburg, Regensburg, Germany(2)
University of Vienna, Vienna, Austria(3)
A multi-omics approach was used to observe changes in gene expression after the induction of an unfolded protein response (UPR) pathway, with parallel study of the transcriptome, proteome and translation changes. By filtering, the induction of 267 genes, many of which were previously not involved in stress response pathways, could be identified. These pathways play a key role in numerous diseases and are involved in cancer growth and chemoresistance.
A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites
Robert Ahrends(1, 3), Jan Medenbach(2)
Added on: 06-23-2020
Novel Alzheimer’s drug candidates
2020
Georg-August University, Göttingen, Germany
The human zinc(II) enzyme glutaminyl cyclase (QC) is suggested to participate in the pathogenesis of Alzheimer’s disease. Using protein crystallography and X-ray structure analyses the authors show snapshots of QC structure and identify hydrazides as highly selective QC inhibitors. Thus, the authors envision a putative use for hydrazydes in Alzheimer's disease, as well as in Huntington's disease and various cancers.
Hydrazides are potent transition-state analogues for glutaminyl cyclase implicated in the pathogenesis of Alzheimer’s disease
Kai Tittmann
Added on: 07-22-2020
Complex tumor model to test drug effects on cancer-associated cell types
2020
University College London, London, United Kingdom
Simple monolayer in vitro cultures restrict the possibilities of drug testing to specific cell types. In this study, a new model is developed with the inclusion of a stromal compartment to reflect the complex multicellular tumor environments. This new model allowed the researchers to describe the effects of the drug Pazopanib on endothelial cell network and renal cell carcinoma cells, showing that this can be a good model to test drugs whose effects are not limited to cancer cells.
The anti-angiogenic tyrosine kinase inhibitor Pazopanib kills cancer cells and disrupts endothelial networks in biomimetic three-dimensional renal tumouroids
Katerina Stamati
Added on: 07-18-2021
Human genetic data and in-silico-approaches reveal new cancer mechanisms
2020
Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
Using highly sensitive analytical methods (whole-genome sequencing, whole-exome sequencing, RNAseq) and in silico methods, human-relevant, clinically highly relevant data were obtained, showing a much higher incidence of chromothripsis than previously assumed. In addition, it has been shown that these genetic events do not only occur at an early stage but also in late stages or in relapses. The prevalence of genomic instability was previously estimated at a few per cent, but in fact, it occurs in half of the tumour samples investigated. Chromosomes break and the parts are either lost or incorrectly reassembled. These events play an important role in the development of cancer.
The landscape of chromothripsis across adult cancer types
Aurélie Ernst
Added on: 06-25-2020
Inhibition of the PLOD2 gene by epigenetic editing
2020
University Medical Center Groningen, Groningen, Netherlands
Epigenetic editing is a new method for correcting pathological gene expressions. The present study investigated how to inhibit the PLOD2 gene, associated with fibrosis and cancer. For this purpose, the effect of DNA methyltransferase M.SssI and the KRAB repressor on PLOD2 expression in human fibroblasts and breast cancer cells was compared and analyzed using various genetic engineering methods. M.SssI induced de novo DNA methylation and altered the histone modifications contextually. Furthermore, a 50%-70% reduction in gene expression of PLOD2 was observed. The alignment of the KRAB repressor, which is routed to the PLOD2 promoter via zinc finger or CRISPR-dCas9-mediated targeting, caused the deposition of repressive histone modifications and resulted in almost complete suppression of PLOD2 expression. In both cases, the expression induced by the growth factor TGF-beta1 could be inhibited. Unstimulated PLOD2 expression, on the other hand, could only be detected by KRAB. In other kidney cancer and breast cancer cell lines, targeting temporarily expressed dCas9-KRAB induced ongoing PLOD2 repression. Based on the results, KRAB-induced heterochromatin enables effective gene compression without DNA methylation, which is simultaneously resistant to activations by TGF-beta1. PLOD2 repression by means of epigenetic editing can, for example, help to prevent tissue fibrosis or the formation of metastases and to develop individualized therapeutic approaches.
KRAB-induced heterochromatin effectively silences PLOD2 gene expression in somatic cells and is resilient to TGFβ1 activation
Marianne G. Rots
Added on: 08-22-2022
Sensitive and specific multi-cancer detection test
2020
US Oncology Research, The Woodlands, USA
Targeted methylation analysis of cell-free DNA (cfDNA) in 6689 cancer patients and healthy volunteers simultaneously detected and localized >50 cancer types, including high-mortality cancers that lack screening paradigms. Cancers were detected across all stages at a specificity of >99%. This targeted methylation approach localized the tissue of origin with >90% accuracy. The goal of this test is to enable early multi-cancer detection.
Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA
Michael V. Seiden
Added on: 05-25-2020
Cancer patients at greater risk from COVID-19 but some therapies can help
2020
Università della Svizzera Italiana, Bellinzona, Switzerland
This epidemiologic study analysed 9280 SARS-Cov-2-positive patients from Italy and shows that cancer patients have an increased risk of SARS-CoV-2 infections than non-cancer patients. However, prostate cancer patients receiving androgen-deprivation therapies appear to be partially protected from SARS-CoV-2 infections.
Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (n=4532)
Andrea Alimonti
Added on: 05-25-2020
Immune sensor TLR8 is crucial for human immune defence
2020
Universitätsklinium Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Bonn, Germany
The activation of the immune sensor TLR8 (Toll-like receptor 8) plays an important role in the human immune defence. That was recently discovered since TLR8 is not active in mice and its crucial role has therefore long been neglected. TLR8 reacts to a broad range of pathogenic RNAs from viruses, bacteria and protozoa. If the gene coding for TLR8 is switched off, the cells no longer recognise bacterial RNA, so that tit plays a crucial role in immune defence. The RNases T1 and 2 were also identified. These break down foreign RNA into a form in which TLR8 can recognise and render it harmless; without their activity, TLR8 does not detect foreign RNA. These interactions were demonstrated using tumor cell lines as well as human cells from patients who have an RNaseT2 gene defect. Based on these findings, new vaccines against infections or immune therapies against cancer could be developed.
Immune sensing of synthetic, bacterial, and protozoan RNA by Toll-like receptor 8 requires coordinated processing by RNase T2 and RNase 2
Eva Bartok
Added on: 05-27-2020
Organoid cultures suitable for long-term breast cancer studies
2020
Harvard Medical School, Boston, USA
The authors present an extensive evaluation of the ability of organoid culture technology to preserve complex stem/progenitor and differentiated cell types via long-term propagation of mammary tissues from healthy people and cancer patients. Single-cell analyses demonstrate that protein expression patterns of the tissue of origin can be preserved in organoid culture. This indicates that organoid cultures provide a valuable platform for studies of mammary differentiation, transformation, and breast cancer risk.
Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages
Joan S. Brugge
Added on: 05-26-2020
Quantum imaging reveals biomolecules
2020
Fraunhofer-Institut für Angewandte Optik und Feinmechanik IOF, Jena, Germany(1)
Fraunhofer-Institut für Physikalische Messtechnik IPM, Freiburg, Germany(2)
Fraunhofer-Institut für Physikalische Messtechnik IPM, Freiburg, Germany(2)
Biosubstances such as proteins, lipids or other chemical elements can be distinguished by their characteristic molecular oscillations. The system uses the quantum mechanical effect of the photon entanglement, which can then be detected and assembled into an image.
In this way, it is possible to determine how certain proteins, lipids or other substances are distributed on a cellular level. For example, some types of cancer have a characteristic accumulation or expression of certain proteins. This would make it possible to detect and combat the disease more efficiently. A more precise knowledge of the distribution of biosubstances could also lead to great progress in drug research.
Andreas Tünnermann(1), Karsten Buse(2)
Added on: 05-26-2020
Tumor-brain organoid interaction model for disease mechanisms and drug discovery
2020
Berlin Institute of Health and Charité, Berlin, Germany
Glioblastoma (GBM) is the most frequent and most aggressive primary brain tumor with low survival rates despite decades of intensive research. Patient-derived GBM cells are used here to study their invasion into and their interaction with human cerebral organoids. Confocal microscopy and single-cell RNA sequencing are used for the analysis. It was shown that tumor cells extend a network of long microtubes within the normal organoids, recapitulating the in vivo behaviour as this tumor aggressively infiltrates the brain via microtubes. A transcriptional program was identified induced by the interactions between normal brain cells and tumor cells, which upregulates genes required for tumor dispersion. Hence, the model is useful for studying GBM invasion and transcriptional heterogeneity in vitro, with applications for both pharmacological screens and patient-specific treatment selection.
Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics
Roland Eils, Christian Conrad
Added on: 01-29-2021
Identification of genes significant for cancer through analysis of sequence databases and publications
2020
Johns Hopkins University, Baltimore, USA
Sequencing is sufficiently inexpensive and rapid that researchers have at their disposal thousands of tumor tissues with RNA-Seq data, providing unprecedented insight into the transcriptional landscape of cancer. However, the sheer volume of data has proven challenging when it comes to deriving biological meaning. Many types of analysis, rely to some degree on a priori knowledge of the pathways, the biological role, or the molecular function of genes. In the present study, the researchers aimed at drawing attention to the fact that a substantial portion of genes statistically associated with cancer biology lack annotations adequate for understanding their role in cancer pathology. The researchers performed database explorations for genes associated with an unfavourable outcome in cancer using the Human Protein Pathology Atlas which contains a correlation of mRNA and clinical outcome for almost 8,000 cancer patients. The study showed that a range of biologically relevant genes is not associated with known published pathways. They also tend not to be linked with known dominant mutations. Further, the researchers did draw gene network maps to point to biological areas which are generally understudied. Overall, the study concludes that there is little relationship between the relative biological importance of genes and the literature dedicated to specific genes, suggesting instead that most genes, after their initial discovery, attract limited attention, while other genes attract disproportionate attention due, at least in part, to social trends and the tendency of the scientific community to be a “small-world”. In the future, the data-driven analysis should help to pinpoint biological "terra incognita" which should be considered as challenges to tackle.
Functionally enigmatic genes in cancer: using TCGA data to map the limitations of annotations
Channing J. Paller
Added on: 12-22-2021
Novel breast-cancer tumor size classification
2020
Department of Radiation Oncology, Medical Center, University of Freiburg, Freiburg, Germany
The study presents a novel classification for the analysis of patients with pre-irradiated locally recurrent breast cancer that allows for the assessment of chances and limitations of combined hyperthermia / re-irradiation in the treatment of different tumor sizes. Applying this classification for the evaluation of 201 patients with pre-irradiated tumors allowed for stratification into distinct prognostic groups, thus helping to guide the decision between curative and palliative intent.
Combined wIRA-Hyperthermia and Hypofractionated Re-Irradiation in the Treatment of Locally Recurrent Breast Cancer: Evaluation of Therapeutic Outcome Based on a Novel Size Classification
Peter Vaupel
Added on: 04-21-2020
Human bone marrow-chip reveals mechanisms underlying genetic disorders
2020
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, USA
Bone marrow cells are cultured from patient cells on a chip. Patients' pathophysiologies are reflected by their corresponding bone marrow cultures. Studies using bone marrow-chips reveal molecular information on genetic disorders. Bone marrow defects were investigated, induced by radiation, medication or genetic defects.
On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
Donald E. Ingber
Added on: 05-05-2020
Combined in-silico and in-vitro technique detects carcinogenesis caused by bacteria
October 2019
Max Planck Institute for Infection Biology, Berlin, Germany
Using a combination of human intestinal epithelial cell culture and computer modelling, it has been possible for the first time to prove that bacteria or their products can cause cancer.
E. coli toxin colibactin can bind to particularly narrow, AT-rich regions of human DNA, as a computer simulation showed, and cause mutations there. The resulting mutation occurs frequently in certain forms of colon cancer. Thus, a kind of genetic fingerprint could be identified, which bacteria leave behind in the DNA. This mutation signature can already be identified in still healthy cells and opens up promising avenues for further studies in the field of cancer prevention.
Colibactin DNA damage signature indicates causative role in colorectal cancer
Thomas F. Meyer
Added on: 06-24-2020
Using deep learning to better understand blood disorders
October 2019
Helmholtz Zentrum München, München, Germany(1)
LMU Munich, Munich, Germany(2)
LMU Munich, Munich, Germany(2)
The authors created a data set containing 18,000 images of individual leukocytes taken from 100 patients diagnosed with acute myeloid leukaemia and from 100 control patients. The specimens were digitized and used to train a deep learning convolutional neural network for leukocyte classification. The network classifies the most important cell types with high accuracy and identifies pathologies with human-level performance. This approach holds the potential to be used as a classification aid for examining much larger numbers of cells in a smear than can usually be done by a human expert. This will allow clinicians to recognize malignant cell populations with lower prevalence at an earlier stage of the disease.
Human-level recognition of blast cells in acute myeloid leukaemia with convolutional neural networks
Carsten Marr(1), Karsten Spiekermann(2)
Christian Matek et al. Nature Machine Intelligence 2019 [274]
Cancer Imaging Archive [275]
Chemie.de [276]
Added on: 12-17-2020
Microfluidic methods in cancer liquid biopsy
2019
National Institute for Research and Development in Microtechnologies, IMT-Bucharest, Bucharest, Romania
The current work provides a general overview of the latest on-chip technological developments for cancer liquid biopsy. Current challenges for their translation and their application in various clinical settings are discussed. Microfluidic solutions for each set of biomarkers are compared, and a global overview of the major trends and ongoing research challenges is given.
Recent advances in microfluidic methods in cancer liquid biopsy
Ciprian Illiescu
Added on: 05-25-2020
Body-on-a-chip device predicts cancer drug responses
Company 2019
Hesperos Inc., Orlando, USA
Using a body-on-a-chip device, researchers from Hesperos, Inc., circulated blood-like fluid through a multi-chamber chip cultured with tissue types as human heart, liver, bone marrow and cancer cells along with anti-cancer drugs to simultaneously assess efficacy and safety. The system correctly identified known adverse effects and could assess the efficacy of different drugs and drug combinations.
Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics
James J. Hickman
Christopher W. McAleer et al. Science Translational Medicine 2019 [279]
Hesperos, Inc. [280]
Physicians Committee for Responsible Medicine [281]
Added on: 05-25-2020
Human platelet lysate as validated alternative to assess chemosensitivity
2019
University Medical Center Mainz, Mainz, Germany
Cell culture experiments represent an in vitro alternative to animal experiments. Fetal calf serum (FCS) is the most commonly used medium supplement worldwide. FCS contains a variable mixture of growth factors and cytokines that support cell proliferation. This undefined nature of FCS is a source of experimental variation, undesired immune responses, possible contaminations. Thus, alternative, defined, valid, and reliable medium supplements should be characterized in a large number of experiments. Human platelet lysate (hPL) is increasingly appreciated as an alternative to FCS. It was unclear whether cells respond differentially to clinically relevant chemotherapeutics inducing replicative stress and DNA damage, induction of reactive oxygen species (ROS), the tyrosine kinase inhibitor imatinib, and novel epigenetic modifiers belonging to the group of histone deacetylase inhibitors. This study shows that cancer cells derived from leukaemia and colon cancer grow very similarly in culture media supplemented with FCS or hPL. Notably, cells have practically identical proteomes under both culture conditions. Moreover, cells grown with FCS or hPL responded equally to all types of drugs and stress conditions that were tested. In addition, the transfection of blood cells by electroporation can be achieved under both conditions. Hence, hPL is a moderately priced substitute for FCS in various experimental settings.
Human platelet lysate as validated replacement for animal serum to assess chemosensitivity
Oliver H. Krämer
Added on: 02-08-2021
Computer prediction of antiproliferative activity of steroidal drugs
2019
University of Novi Sad, Novi Sad, Serbia
Computational analysis of the effectivity of antiproliferative drugs derived from 17α-picolyl and 17(E)-picolinylidene against human ER-breast adenocarcinoma cells is presented. With these tools, it is possible to rank the compounds based on their anticancer activity, lipophilicity, ADME profile and one can predict their antiproliferative activity. These results show that the methods presented in this study will allow for better selection, synthesis and rational design of new potential drugs.
Toward steroidal anticancer drugs: Non-parametric and 3D-QSAR modeling of 17-picolyl and 17-picolinylidene androstanes with antiproliferative activity on breast adenocarcinoma cells
Strahinja Z Kovačević
Strahinja Z Kovačević et al. Journal of Molecular Graphics and Modelling 2019 [283]
EURL ECVAM [284]
Added on: 07-27-2021
Human fallopian tube organoid model for studies of chronic chlamydia infections
2019
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
The authors developed a human fallopian tube organoid model for the analysis of chronic chlamydia infections. Infected organoids exhibit a less differentiated phenotype with higher stemness potential, as well as a higher degree of DNA hypermethylation. These results suggest a long-term impact on the epithelium and imply a link to ovarian cancer.
Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation
Thomas F. Meyer
Added on: 05-22-2020
In vitro blood vessels as a model for anti-angiogenic drug response testing
2019
Wisconsin Institutes for Medical Research, University of Wisconsin, Madison, USA
A three-dimensional platform was created using tissue from healthy people and patients with kidney tumors, which reflects the blood supply to the tumors. In this way, the efficacy of anti-angiogenic therapies can be assessed for each an individual patient.
Patient-specific organotypic blood vessels as an in vitro model for anti-angiogenic drug response testing in renal cell carcinoma
David J. Beebe
Added on: 05-25-2020
Lung cancer organoids from pleural effusion aspirate
2019
Wake Forest School of Medicine, Winston-Salem, USA
In this study, the use of 3D hydrogel-based lung cancer organoids derived from pleural effusion aspirate from multiple lung cancer patients is demonstrated. The resulting organoids preserve the phenotype of the cancer cells as well as maintain cancer and stromal cell interactions. Patient-derived cells placed directly into hydrogel-based organoids created anatomically relevant structures and exhibited lung-cancer-specific behaviour. On the other hand, cells first grown in plastic dishes and then cultured in 3D did not create similar structures. Moreover, chemotherapeutic responses of patient-derived cells were compared for 2D and 3D cell culture systems. Cells in 2D culture were more sensitive to treatment when compared with 3D organoids. Organoids from pleural effusion fluid of lung cancer patients display in-vivo-like anatomy and drug response and thus could serve as more accurate disease models for the study of tumour progression and drug development.
Pleural effusion aspirate for use in 3D lung cancer modeling and chemotherapy screening
Shay Soker
Added on: 03-25-2022
100 cancer organoid models
2019
Wellcome Sanger Institute , Hinxton, United Kingdom
Researchers at the Wellcome Sanger Institute have developed 100 cancer organoids. The organoids will soon be available for researchers, together with associated data including whole genome sequences, aiding cancer research, and drug discovery. Having 100 organoids from patients with three types of cancer reflect the huge diversity of tumors.
100 cancer organoid models developed by Sanger Institute scientists
Mathew Garnett
Added on: 05-22-2020
3D brain cancer platform for personalized medicine
Company 2019
MicroMatrices Associates Ltd, Dundee, United Kingdom
A high throughput histology platform was applied for testing drugs against tumors in a novel 3D heterotypic glioblastoma brain sphere model consisting of glioblastoma tumor cells, iPSC-derived neurons, glial cells and astrocytes grown in a spheroid. This platform provides a novel approach for screening new anti-glioblastoma agents and evaluating different treatment options for a given patient.
A human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine
Simon Plummer
Added on: 05-25-2020
Computational assessment of tumor heterogeneity
2019
Stanford University School of Medicine, Stanford, USA
The computational model presented in this study allows assessing tumor heterogeneity and clonal replacement throughout treatment. It was used to study five human breast cancer tumors treated with HER2-targeted therapy. This model is able to show that two of these tumors underwent clonal replacement and that the resistant subclones were present before the beginning of the treatment and their rate of resistance-related genomic changes. This model is a valuable new tool when trying to understand the development of treatment resistance.
Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy
Christina Curtis
Added on: 07-20-2021
Immune response analysis to immunotherapy in cervical cancer patients' tissues
2019
Cancer Center Amsterdam, Amsterdam, Netherlands
Cervical cancer (CxCa) is still the second most diagnosed cancer among women worldwide, its development is associated with the suppression of T-cell responses against human papillomavirus (HPV). Although many clinical trials have shown that releasing immunosuppressive brakes on effector T cells, like programmed cell death−ligand-1 (PD-(L)1), leads to responses in various cancer types; no reliable biomarkers predictive of clinical response on PD-1 blockade have been identified yet. In the present study, the researchers aimed at identifying immunotherapeutic targets on T cells performing flow cytometry profiling on T cells from patients' tumors. The data revealed that local PD-(L)1 blockade could interrupt loco-regional immune suppression in CxCa. Furthermore, the data identify a specific subset of T cells as therapeutic targets, which may also serve as a predictive biomarker for PD-(L)1 checkpoint blockade.
Efficacy of PD-1 blockade in cervical cancer is related to a CD8+FoxP3+CD25+ T-cell subset with operational effector functions despite high immune checkpoint levels
T. D. de Gruijl
Added on: 09-17-2021
Possible tumour suppressor investigated in triple-negative breast cancer cells
2019
Dongtai People’s Hospital,, Dongtai, China
Triple-negative breast cancer remains one of the most aggressive breast cancers in women. Some studies suggested that miR-361-5p is downregulated in breast cancer, but its role in triple-negative breast cancer is still unclear. Here, tissue samples from patients and human triple-negative breast cancer cells were used to study the potential of miR-361-5p as tumor suppressor and its signalling mechanisms. The results confirmed that miR-361-5p targets the RQCD1 gene. Moreover, tissue samples from patients had low levels of miR-361-5p and high levels of RQCD1. Furthermore, cells treated with miR-361-5p mimics inhibited expression and phosphorylation of cancer-related factors and suppressed cell viability and invasion of cancer cells. Overall, the researchers show that overexpression of miR-361-5p may result in tumor suppressor activity in triple-negative breast cancer cells by targeting RQCD1 and its signaling pathway.
Overexpression of miR-361-5p in triple-negative breast cancer (TNBC) inhibits migration and invasion by targeting RQCD1 and inhibiting the EGFR/PI3K/Akt pathway
Xuefeng Zhou
Added on: 11-01-2021
Propofol modulates mammosphere formation of breast cancer cells
2019
Key Laboratory of Cancer Prevention and Therapy, Tianjin, China(1)
Tianjin Medical University Cancer Institute and Hospital, Tianjin, China(2)
Tianjin Medical University Cancer Institute and Hospital, Tianjin, China(2)
Recent studies have described that propofol can hinder cancer progression through the inhibition of cancer cell proliferation. Despite being a minor population in tumours, cancer stem cells have a crucial role in cancer progression and relapse after treatment. Here, human breast cancer cells were cultured in 2D and 3D to study in vitro the effects of propofol on breast cancer stem cells. The results show that propofol could reduce the ability of mammosphere formation and downregulates the expression of PD-L1 and Nanog. Furthermore, propofol had no effect on PD-L1 knockout breast cancer stem cells. Overall, the researchers demonstrate that propofol can inhibit mammosphere formation of breast cancer stem cells in vitro, potentially through the modulation of PD-L1.
Propofol reduced mammosphere formation of breast cancer stem cells via PD-L1/Nanog in vitro
Yue Yu(1), Hongwei Zhao(2)
Added on: 10-27-2021
3D bioprinted metastatic tumor microenvironment models
2019
Department of Mechanical Engineering, University of Minnesota, Minneapolis, USA
Vascularized tumor models are created via 3D bioprinting techniques to mimic key steps of cancer dissemination (invasion, intravasation, and angiogenesis), based on guided migration of tumor cells and endothelial cells in the context of stromal cells and growth factors. The utility of the metastatic models for drug screening is demonstrated by evaluating the anticancer efficacy of immunotoxins. These 3D vascularized tumor tissues provide a proof-of-concept platform to i) fundamentally explore the molecular mechanisms of tumor progression and metastasis, and ii) preclinically identify therapeutic agents and screen anticancer drugs.
3D bioprinted in vitro metastatic models via reconstruction of tumor microenvironments
Michael C. McAlpine
Added on: 05-25-2020
Biofabrication of human breast epithelial spheroids
2019
Drexel University, Philadelphia, USA
3D human cancer models are growing in popularity, as they recapitulate better than 2D cultures several characteristics of the in vivo microenvironment. However, biofabrication techniques are still time-consuming and depend on complex cellular interactions within the model components. Thus, preformed 3D spheroids using alginate-based bioinks could be useful to create models that overcome some of these limitations. Here, human breast epithelial cell lines were bioprinted individually or in pre-formed spheroids of different bioinks in monoculture or co-culture with human endothelial cells. The results showed that individually printed breast cells formed spheroids only in Matrigel-based bioinks. Nevertheless, pre-formed spheroids maintained their normal cellular features and were more resistant to paclitaxel when cultured without endothelial cells. Overall, the researchers propose a simplified biofabrication approach for 3D modelling of human breast cancer that can rapidly recapitulate tumor microenvironment characteristics for drug screening or mechanistic studies.
Bioprinting of 3D breast epithelial spheroids for human cancer models
Alisa Morss Clyne
Added on: 10-12-2021
Improved in vitro model of bone metastasis
2019
East China Jiaotong University, Nanchang, China(1)
Tianjin University, Tianjin, China(2)
Tianjin University, Tianjin, China(2)
Construction of a biomimetic 3D scaffold of PLGA nanofibers incorporating hydroxyapatite to more consistently recapitulate the skeletal microenvironment in vitro during metastasis. In these scaffolds the properties of human breast cancer cells correlate better with the in vivo cell behaviour, confirming the biocompatibility of this model and the suitability of this model as a new platform for 3D cancer cell culture.
Incorporation of hydroxyapatite into nanofibrous PLGA scaffold towards improved breast cancer cell behavior
Quanchao Zhang(1), Yizao Wan(2)
Added on: 07-14-2021
In vitro testing of antibody-drug conjugate in human cell lines
Company 2019
Catalent Biologics, Emeryville, USA
Immune checkpoint inhibitors in combination with chemotherapeutic drugs have been very promising yet these agents are systemically delivered and cytotoxic to all proliferating cells. Conjugating drugs with specific antibodies might induce immunogenic cell death in targeted cancer cells. In the present study, the researchers examined the response to antibody-drug conjugate treatment in human cell lines by using a set of in vitro markers. The results indicated that antibody-drug conjugates can selectively elicit hallmarks of immunogenic cell death on target antigen-expressing cells but not antigen-negative cells.
Maytansine-bearing antibody-drug conjugates induce in vitro hallmarks of immunogenic cell death selectively in antigen-positive target cells
David Rabuka
Added on: 07-29-2021
Potential importance of B cells in immune response tested ex vivo in patients' tissues
2019
University of Cologne, Cologne, Germany
The composition and function of B lymphocytes, crucial players in cancer immune response, in head and neck squamous cell carcinoma (HNSCC) has not been well described yet. In the present study, the researchers analyzed B cell subsets from donor tissues by flow cytometry. Also, the humoral immune responses were analyzed in vitro against different tumor-associated antigens (TAA). In view of the increasing use of immunotherapeutic approaches, it will be important to include B cells in comprehensive phenotypic and functional analyses of tumor-associated lymphocytes.
Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma
Dirk Beutner
Added on: 07-29-2021
Quantitative immunocytochemistry method to improve patient's response prediction
Company 2019
Navigate BioPharma Services, Inc., Carlsbad, USA(1)
The First Affiliated Hospital of Xiamen University, Fujian, China(2)
The University of Texas MD Anderson Cancer Center, Houston, USA(3)
The First Affiliated Hospital of Xiamen University, Fujian, China(2)
The University of Texas MD Anderson Cancer Center, Houston, USA(3)
Programmed cell death protein 1 (PD-1) is an immune checkpoint targeted by some anti-cancer treatments. Yet, the efficiency of the response can vary greatly and there is a need for biomarkers to better predict patient's response. In the present study, the researchers analyzed tumor tissue samples from 414 patients with B-cell lymphoma using quantitative immunocytochemistry 3 markers related to PD-1 in parallel with survival analysis of the patients. The results show the potential for quantitative immunocytochemistry for better patient's response prediction.
PD-1/PD-L1 expression and interaction by automated quantitative immunofluorescent analysis show adverse prognostic impact in patients with diffuse large B-cell lymphoma having T-cell infiltration: a study from the International DLBCL Consor
Christine A. Vaupel(1), Bing Xu(2), Ken H. Young(3)
Added on: 07-28-2021
Sensitive method to detect the presence of memory T cells in skin cancer patients
2019
National Institutes of Health, Bethesda, USA
T cells targeting shared oncogenic mutations can induce durable tumor regression in epithelial cancer patients and could potentially be used to develop personalized cancer immunotherapy. Unfortunately, detection of cells in the peripheral blood of patients with the common metastatic epithelial cancer patients is unknown. In the present study, the researchers used a highly sensitive in vitro stimulation and cell enrichment of peripheral memory T cells from six metastatic cancer patients. Memory T cells targeting unique, as well as shared somatic mutations, could be detected. The results should pave the way for developing personalized immunotherapy.
Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients
Steven A. Rosenberg
Added on: 07-28-2021
Study of immune response in a large cohort of breast cancer patients
2019
Zealand University Hospital, Slagelse, Denmark
Patients with a BRCA1 or BRCA2 mutation (BRCA-mutated breast cancer) are frequently diagnosed with low differentiated and highly proliferating breast cancer characterized by high amounts of tumor-infiltrating lymphocytes (Tils). Yet, the prognostic importance of Stromal Tils (sTils) in BRCA-mutated breast cancers is unknown. In this study, the researchers investigated sTils in a nationwide Danish cohort of BRCA1/2 carriers with primary breast cancer in terms of prevalence in sTils groups correlated with survival. STils were quantified on fixed tumor tissues from the patients. Breast cancer patients with a germline BRCA mutation had higher sTils than previously reported in sporadic breast cancers, and sTils were associated with favourable survival among BRCA carriers. In conclusion, BRCA breast cancers show high activation of the immune system and an increasing amount of sTils are associated with lower mortality.
Evaluation of tumor-infiltrating lymphocytes and association with prognosis in BRCA-mutated breast cancer
I.M.H. Sønderstrup
Added on: 07-28-2021
Cancer modeling meets human organoid technology
2019
Cold Spring Harbor Laboratory, Cold Spring Harbor, USA(1)
Oncode Institute and Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, Netherlands(2)
Oncode Institute and Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, Netherlands(2)
The authors review the current state and future prospects of the rapidly evolving tumor organoid field.
Cancer modeling meets human organoid technology
David Tuveson(1), Hans Clevers(2)
Added on: 05-25-2020
3D microfluidic multicellular tumor model to study metastasis
December 2018
Massachusetts Institute of Technology, Cambridge, USA
Recent studies have shown hypoxia to be a characteristic of tumor microenvironment and a trigger of tumor cell invasion. However, it is difficult to replicate tumor tissues in vitro due to current limitations. However, microfluidic models have become a popular tool to study individual factors in complex environments. Here, a microfluidic chip is used to study the role of hypoxia-inducible factors in the potential extravasation of human breast cancer cells growing around a microvascular network. The results showed that hypoxia-inducible factor 1 alpha was increased in hypoxic conditions and correlated with the modulation of cell behaviour, which lead to an increase in the extravasation rate. When the hypoxia-inducible factor 1 alpha was knocked-down, it was possible to block the metastatic behaviour. Overall, the researchers propose a new model that can help to elucidate the importance of hypoxia in tumor progress and metastasis and decipher the underlying mechanisms that drive this interplay.
A 3D microvascular network model to study the impact of hypoxia on the extravasation potential of breast cell lines
Roger D Kamm
Added on: 10-09-2021
3D-printed microfluidic platform for the analysis of tumor microenvironments
December 2018
Microsystems Technology Laboratories, Massachusetts Institute of Technology, Cambridge, USA
A 3D printed chip made from biocompatible resin enables biopsied tumor fragments to survive much longer than before. Medicines can be applied to the system via various connections and channels and the reactions of the tumor cells can be examined.
Monolithic, 3D-printed microfluidic platform for recapitulation of dynamic tumor microenvironments
Luis Fernando Velásquez-García
Ashley L. Beckwith et al. Journal of Microelectromechanical Systems 2018 [318]
Technology Networks [319]
Added on: 05-25-2020
Computational prediction of key processes in tumor progression
December 2018
Duke University School of Medicine / Duke Cancer Institute, Durham, USA(1)
Rice University, Houston, USA(2)
Rice University, Houston, USA(2)
In this study, the authors focus on trying to model the epithelial-mesenchymal transition and the formation of cancer stem cells in tumor progression by using a computational simulation. Using this method, they identify a signaling pathway that shows to be important in tumor organoid formation.
Toward understanding cancer stem cell heterogeneity in the tumor microenvironment
Gayathri R. Devi(1), José Nelson Onuchic(2), Herbert Levine(2), Mohit Kumar Jolly(2)
Added on: 07-03-2021
Machine learning approach for breast cancer diagnostics
December 2018
University of Pennsylvania, Philadelphia, USA
A machine learning approach coupled with multimodal ultrasound images is applied to improve breast cancer diagnosis. Several properties obtained from the quantitative evaluation of proven solid breast lesions were used to select statistically significant features that can be valuable for diagnostics. This method not only allows to achieve high efficacy for breast cancer diagnosis, but can also identify the weakly learned cases that can disturb the correct diagnosis.
Machine learning to improve breast cancer diagnosis by multimodal ultrasound
Chandra M Sehgal
Added on: 07-30-2021
Microfluidic 3D model to study solid tumor treatment efficiency
December 2018
University of Wisconsin, Madison, USA
Solid tumors present several difficulties when designing treatment strategies, including immunotherapies. The mechanisms underlying the action of different therapies against solid tumors remain elusive to study because of the limitations of currently available in vitro models. Here, a new microfluidic model is developed with 3D human breast cancer spheroids embedded in a 3D extracellular matrix and flanked by lumens lined with human endothelial cells. In this model, the results showed that perfused antibodies could rapidly diffuse into the matrix but were unable of penetrating the spheroid. However, natural killer cells were able to target the tumor and penetrate to the innermost layer attacking tumor cells. When both approaches were combined, cytotoxicity in the periphery of the tumor spheroid was enhanced. In this study, the researchers develop a new model that shows to be a potential tool to investigate the efficiency of immunotherapy in solid tumors.
Evaluating natural killer cell cytotoxicity against solid tumors using a microfluidic model
Jose M Ayuso
Added on: 10-05-2021
Microfluidic device to investigate targeted drug delivery systems
December 2018
Johns Hopkins University, Baltimore, USA
In recent years, there has been a big effort to develop efficient strategies to deliver antitumor therapeutic agents. The lack of understanding of the mechanisms underlying the transport of targeted drugs to tissue-specific sites is a crucial limitation. Thus, there is a need to improve in vitro platforms to better recapitulate the key aspects of the delivery of antitumor drugs while overcoming the complexity of in vivo modelling. Here, a 3D microvessel is developed using human endothelial cells positioned around a cylinder and surrounded by an extracellular matrix containing human breast cancer cells to model tumor microenvironment and study the differences between free doxorubicin or a liposomal formulation of this drug. The results show that the method of drug delivery influences transendothelial migration and tumor uptake. Moreover, it was possible to study the kinetics of the drugs and investigate the mechanisms of drug transport through the endothelium. Overall, the researchers propose a model that can be customized to replicate specific tumor microenvironments and better understand and optimize different drug delivery systems.
Chemotherapeutic drug delivery and quantitative analysis of proliferation, apoptosis, and migration in a tissue-engineered three-dimensional microvessel model of the tumor microenvironment
Peter C Searson
Added on: 10-19-2021
Microfluidic organ-on-chip device to assess anti-tumor drug response
December 2018
Paris Sciences et Lettres Research University, Paris, France
The tumor microenvironment has been shown to have a key role in cancer progression. Lately, in vitro organ-on-chip technologies have been gaining popularity to integrate multicellular models that allow to better recapitulate the in vivo conditions. Here, a 3D co-culture microfluidic device based on organ-on-chip methods is used to culture ex vivo HER2+ human breast cancer samples together with other cell types commonly present in the in vivo environment. The results show that treating with trastuzumab replicated the anti-tumoral antibody-dependent cell-mediated toxicity immune response. However, cancer-associated fibroblasts were able to antagonize the effects of the drug. Altogether, the researchers present a new model that can be used to study ex vivo the drug response in an immunocompetent tumor microenvironment to assess the potential drug response of certain therapeutic strategies.
Dissecting effects of anti-cancer drugs and cancer-associated fibroblasts by on-chip reconstitution of immunocompetent tumor microenvironments
Maria Carla Parrini
Added on: 10-05-2021
New HER2-detection method assessed in 2D and 3D models
December 2018
University of Rochester Medical Center, Rochester, USA
The study describes the development of a fluorescent nanoparticle-based method to quantify HER2 in breast cancer patient samples and to assess potential treatments. Using monolayer cultures and paraffin-embedded patient biopsies, the researchers compare the efficacy of this new method relative to immunohistochemistry and in situ hybridization. The results show that this method not only improves HER2 quantification, but that this can lead to a better subsetting of breast cancer patients.
A novel detection methodology for HER2 protein quantitation in formalin-fixed, paraffin embedded clinical samples using fluorescent nanoparticles: an analytical and clinical validation study
David G Hicks
Added on: 07-21-2021
Nextstrain: real-time tracking of pathogen evolution
December 2018
Fred Hutchinson Cancer Research Center, Seattle, USA
Nextstrain is an open-source project to harness the scientific and public health potential of pathogen genome data. It provides a continually-updated view of publicly available data for certain important pathogens such as SARS-CoV-2, influenza, Ebola, and Zika viruses, with powerful analytics and visualizations showing pathogen evolution and epidemic spread. Nextrstrain’s goal is to aid epidemiological understanding and improve outbreak response.
Nextstrain: real-time tracking of pathogen evolution
James Hadfield
Added on: 11-06-2020
Proteomic analysis identifies mechanisms related to chemoradiation resistance
December 2018
Institute of Molecular Medicine and Cell Research, Freiburg, Germany
Tha authors analyzed the tumor proteomes of primary pancreatic ductal adenocarcinoma (PDAC) patients subjected to additive chemoradiation after surgical resection. Results from patients achieving short versus prolonged progression-free survival are compared. The study investigates the responsiveness of PDAC patients to chemoradiation and provides further evidence for a role of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) in therapy resistance.
Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance
Oliver Schilling
Added on: 04-21-2020
Spheroid model of ovarian cancer enables testing of hormone regulation and signaling of metastasis
December 2018
Indian Institute of Science, Bengaluru, India
In vitro spheroid model of ovarian cancer was generated from patients ascites and primary tumor tissues. This model was shown to be regulated by follicle-stimulating hormone (FSH) through Notch signaling. Spheroid formation and cell proliferation was blocked in vitro using FSH and Notch antagonistic antibodies. Thus, Notch and FSH are potential immunotherapeutic targets for ovarian cancer treatment.
Follicle-stimulating hormone is an autocrine regulator of the ovarian cancer metastatic niche through notch signaling
Ramray Bhat, Rajan Dighe
Added on: 07-06-2021
The Virtual Cancer Patient
December 2018
Technische Universität Darmstadt, Darmstadt, Germany
The project "The Virtual Cancer Patient" takes into account the problem that every individual cancer patient has a unique disease due to individual genetic changes. The aim of the project is to create a network from human gene and protein data, which can use algorithms to assess in advance whether a particular therapy can help individual patients.
Der virtuelle Krebspatient
Heinz Koeppl
Added on: 04-30-2020
3D culture with breast cancer matrix-based scaffolds
November 2018
Inner Mongolia Hospital, Hohhot, China(1)
Inner Mongolia University, Hohhot, China(2)
Inner Mongolia University, Hohhot, China(2)
Breast cancer extracellular matrices are used as 3D culture scaffolds by decellularizing human breast cancer biopsies. When recellularizing control or diseased extracellular matrices with human breast cancer cells, breast cancer-obtained matrices induce cancer-related behaviours, whereas control samples block those same behaviours. Thus, the use of decellularized cancer-related extracellular matrices in 3D culture modelling can be a powerful tool for breast cancer preclinical research.
Decellularized breast matrix as bioactive microenvironment for in vitro three-dimensional cancer culture
Yuzhen Ma(1), Yanfeng Dai(2)
Added on: 07-20-2021
3D tunable extracellular matrix to study cell migration
November 2018
Michigan State University, Lansing, USA(1)
University of Michigan Medical School, Ann Arbor, USA(2)
University of Michigan Medical School, Ann Arbor, USA(2)
The microstructure of the extracellular matrix has a relevant role in facilitating tumour cell invasion. Specifically, the aligning of type I collagen fibres has been shown to be critical for the migration of stromal and cancer cells. There are several physical cues in fibrillar collagen that may have an influence in regulating cell migration, but it is difficult to analyse them independently within the collagen networks. Here, two types of nanomolecules are used to induce different gelling mechanisms of collagen/alginate to form an in vitro tumour model based on a 3D extracellular matrix. This allows to tune different physical parameters to study how stromal fibroblasts modulate collagen structure to control human breast cancer cell migration. The results show that is possible to generate different fibrillar microstructures while maintaining similar physical characteristics. Moreover, spheroids of human mammary fibroblasts remodel the collagen matrix, depending on the fibrillar microstructure, to facilitate the migration of invasive tumour cells. Overall, the researchers propose a new platform to elucidate how biophysical properties of tumour environments modulate key mechanisms in cancer progression.
Mammary fibroblasts remodel fibrillar collagen microstructure in a biomimetic nanocomposite hydrogel
Andre Lee(1), Gary D Luker(2)
Added on: 10-06-2021
Biofabricated multicellular 3D breast cancer model
November 2018
University of Nebraska Medical Center, Omaha, USA
The content of the study is the biofabrication of a multicellular 3D model to improve drug resistance studies in breast cancer. The model is built with hydrogel bioinks combined with human adipose-derived mesenchymal stromal cells and human HER2+ breast cancer cells. Compared to 2D co-culture models, this new model shows higher resistance to doxorubicin treatment. Additionally, different modifications of the 3D bioprinted constructs influence the capacity of drug resistance of the model. Finally, it was possible to increase drug sensitivity through a lysyl oxidase inhibitor. Overall, this 3D model shows several advantages compared to currently available models to understand breast cancer pathology and explore different therapeutic strategies.
3D bioprinting of breast cancer models for drug resistance study
Bin Duan, Vimla Band
Added on: 07-27-2021
In silico and in vitro assessment of tumor mutational burden
November 2018
University Hospital Heidelberg, Heidelberg, Germany
Assessment of Tumor Mutational Burden (TMB) is essential for response stratification of cancer patients treated with immune checkpoint inhibitors. TMB approximates the number of neoantigens that potentially are recognized by the immune system. As far as now, TMB assessment has been done by whole-exome sequencing which implementation in diagnostics is hampered by tissue availability as well as time and cost constraints. In the present study, the researchers have used in silico and sequencing analysis of commercially available panels of genes in cancer patients tissues. The data suggest that TMB approximation using gene panel sequencing of tumor tissue is feasible and can be implemented in routine diagnostics.
Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real-life analysis of three larger gene panels
Albrecht Stenzinger
Added on: 07-27-2021
Microfluidic platform to study extravasation of cancer cells
November 2018
Istituto Ortopedico Galeazzi, Milano, Italy(1)
Singapore-MIT Alliance for Research and Technology, Singapore, Singapore(2)
Singapore-MIT Alliance for Research and Technology, Singapore, Singapore(2)
The interplay between cancer tumour cells and tissue-specific cells is key for the development of metastases. Specifically, the transmigration of tumour cells through the endothelium and their establishment in a foreign tissue. However, current in vitro models fail in replicating these complex interactions and often lack physiological relevance. Here, a microarray analysis of extravasated human breast cancer cells was coupled with the development of a multicellular microfluidic platform of human cancer cells, endothelium and bone-mimicking environment to study the extravasation potential of human cancer cells from different tissues. The results showed that extravasation is characterised by an up-regulation of late-metastatic markers together with proteases involved in the shedding of the endothelium's glycocalyx. Moreover, the microfluidic platform highlighted that the bone-mimicking microenvironment increased metastasis-related features in three different cancer cell types with different intensities, replicating the in vivo characteristics of these cancer types. Overall, the researchers elucidate some mechanisms related to cancer cell extravasation and propose a new microfluidic platform that can help understand the extravasation potential of different cancer cell types in tissue-specific environments.
A combined microfluidic-transcriptomic approach to characterize the extravasation potential of cancer cells
Matteo Moretti(1), Giulia Adriani(2)
Added on: 10-19-2021
Personalized cancer drug screening using 3D appendiceal tumor organoids
November 2018
Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, USA
The authors generated patient-specific appendiceal cancer tumor organoid models using tissue from biopsies. This model was used for the screening of multiple chemotherapeutics in order to find the best drug for each individual patient.
Appendiceal cancer patient-specific tumor organoid model for predicting chemotherapy efficacy prior to initiation of treatment: a feasibility study.
Aleksander Skardal
Added on: 05-22-2020
Development of 3D printed scaffolds for breast cancer stem cell models
October 2018
University of Girona, Girona, Spain
Standardisation of a printing protocol for polylactic acid scaffolds is described to optimise human breast cancer stem cell culture. After trying several configurations of Fused Filament Fabrication 3D printer, the researchers found that it was possible to have higher proliferation and enhanced populations of ALDH+ cells compared to classical 2D monolayer cultures, having a more physiologically accurate microenvironment to the "in vivo" standards. The results show that this new approach could be a good tool to culture human breast cancer stem cells.
Screening of additive manufactured scaffolds designs for triple negative breast cancer 3D cell culture and stem-like expansion
Joaquim Ciurana, Teresa Puig
Added on: 07-27-2021
Hyaluronan modulates breast cancer cell cycle
October 2018
Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
Clinical evidence suggests that quiescent disseminated tumour cells can remain for a long time in the bone marrow influenced by the microenvironment. Hyaluronan is a major component of the bone marrow extracellular matrix and has been shown to regulate cancer cell and metastasis behaviour. Here, human breast cancer cells in 2D and 3D setups were used to test whether hyaluronan promotes breast cancer quiescence. The results showed that hyaluronan altered the cell cycle of metastatic cancer cells prolonging the G0/G1 phase through the modulation of ERK/p38 signalling pathways. Additionally, it was elucidated that there was an induction of p21cip1 expression together with a decrease in Cyclin D1 levels, which was confirmed in a 3D model together with low Ki-67 expression. Overall, the researchers verify that hyaluronan is a modulator of the cell cycle in 2D and 3D contexts and could contribute to cancer cell quiescence in the bone marrow.
Hyaluronan arrests human breast cancer cell growth by prolonging the G0/G1 phase of the cell cycle
Feng Gao
Added on: 10-27-2021
New 3D tumor model for cancer drug discovery
October 2018
Dalian University of Technology, Dalian, China
In this paper they use decellularized lung scaffolds to re-populate them with breast cancer cells to use it as a 3D breast cancer model. When compared to 2D model systems, this new 3D model shows to be more suitable for drug testing.
A novel tissue-engineered 3D tumor model for anti-cancer drug discovery
Kedong Song
Added on: 07-02-2021
Plant extract to suppress metastatic cell behaviour
October 2018
School of Biosciences, Cardiff, United Kingdom
The hepatocyte growth factor can have pro-metastatic activity through the activation of the c-Met receptor. Recently, this signalling pathway has been described to be important in breast cancer progression and is linked to poor prognosis. Several studies have shown that plants from the genus Boswellia can have anti-cancer activity. Here, two triple-negative human breast cancer cell lines were used to study the effects of extracts of Boswellia frereana on several cancer- and metastasis-related features under stimulation of hepatocyte growth factor. The results showed that the hepatocyte growth factor induced an increase in several metastasis-related processes and c-Met activation in human cancer cells. However, there were no differences in the proliferation rate or spheroid formation of these cells. Upon treatment with the plant extract, the effect of hepatocyte growth factor was inhibited due to the extract-mediated inhibition of c-Met receptor tyrosine kinase phosphorylation. In this study, the researchers reveal a new potential drug candidate that suppresses the hepatocyte growth factor-mediated metastatic behaviour in human breast cancer cells.
Boswellia frereana suppresses HGF-mediated breast cancer cell invasion and migration through inhibition of c-Met signalling
Christian Parr
Added on: 10-18-2021
Targeted cancer therapies double the survival chances of patients
CompanyOctober 2018
IndivuTest GmbH, Hamburg, Germany
A proof-of-concept study was conducted to assess whether patients with advanced-stage IV cancer for whom predominantly no standard therapy was available could benefit from comprehensive molecular profiling of their tumor tissue to provide targeted therapy. Tumor samples of 83 patients were collected under highly standardized conditions and analyzed using immunohistochemistry, next-generation sequencing and phosphoprotein profiling. Based on molecular profiling, targeted therapies were decided by the attending oncologist. Accordingly, 28 patients who met the defined criteria fell into two equal-sized groups. One group received targeted therapies while the other did not. Following six months of treatment, disease control was achieved by 49% of patients receiving targeted therapy and 21% of patients receiving non-targeted therapy Individual patients experienced dramatic responses to a therapy that otherwise would not have been applied. This approach clarifies the value of multi-omic molecular profiling for cancer diagnostics.
Multi-omic based molecular profiling of advanced cancer identifies treatable targets and improves survival in individual patients
Alexandra Samsen
Added on: 06-21-2021
A mathematical model to predict immune system response to CAR-T cell therapy
2018
Friends Select School, Philadelphia, USA(1)
Villanova University, Villanova, USA(2)
Villanova University, Villanova, USA(2)
CAR-T cell therapy is a novel therapy which can be used to treat blood cancers. However, CAR-T cells can cause a life-threatening side-effect called Cytokine Release Syndrome (CRS). The study uses a mathematical simulation to quantify the dynamics of 9 major cytokines for CAR-T cell therapy. The simulation results from this work can be used to generate hypotheses to optimize cytokine inhibition approaches in future experimental research to improve response to CAR-T cell therapy.
A model-based investigation of cytokine storm for T-cell therapy
Yiming Pan(1), Nan Fang(1), Brooks Hopkins(2), Zuyi Hang(2), Matthew Tucker(2)
Added on: 07-06-2021
Classification and mutation prediction from non–small cell lung cancer histopathology images using deep learning
2018
Applied Bioinformatics Laboratories, New York University School of Medicine, New York, USA(1)
Department of Population Health and the Center for Healthcare Innovation and Delivery Science, New York, USA(2)
Department of Population Health and the Center for Healthcare Innovation and Delivery Science, New York, USA(2)
A deep convolutional neural network (inception v3) was trained on more than 1.600 whole-slide images obtained from The Cancer Genome Atlas to automatically classify them into adenocarcinoma, squamous cell carcinoma or normal lung tissue with 97% accuracy. Furthermore, the network can predict the ten most commonly mutated genes in adenocarcinoma with an accuracy of 73 to 86%. These findings suggest that deep-learning models can assist pathologists in the detection of cancer subtype or gene mutations. This approach can be applied to any cancer type, and the code is available at https://github.com/ncoudray/DeepPATH.
Classification and mutation prediction from non–small cell lung cancer histopathology images using deep learning
Aristotelis Tsirigos (1), Narges Razavian(2)
Added on: 04-21-2020
Ex vivo immune response comparison between primary and metastatic tissues of cancer patients
2018
Yale University, New Haven, USA
A better understanding of immune microenvironment evolution during breast cancer progression is needed to design better therapies. In this study, the researchers compared primary tumors and metastasic tissues from breast cancer patients in terms of tumor-infiltrating lymphocyte count and programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry and mRNA levels of 730 immune-related genes. The data suggest that metastatic breast cancer cells evade immune surveillance through multiple mechanisms including downregulation of a broad range of chemotactic and immune-activating cytokines, decreased antigen presentation leading to an immune-cell-depleted microenvironment and upregulation of immunosuppressive and immune evasion mechanisms that result in an inert immune environment. These results predict that immune therapy may be more successful in early-stage breast cancers rather than in metastatic disease. Also, the researchers identified several targets that are present in metastatic breast cancers and could provide the foundation for rational immunotherapy combination strategies.
Immunological differences between primary and metastatic breast cancer
L. Pusztai
Added on: 07-29-2021
Hyaluronan scaffolds for 3D lung tumor spheroids
2018
University of Aveiro, Aveiro, Portugal
In recent years, there is a growing interest in 3D multicellular tumor spheroids that can reproduce complex tumor microenvironments in vitro. However, in vitro 3D lung tumor models that faithfully reproduce their in vivo counterparts are still lacking. Here, a multicellular 3D model was developed co-culturing human lung adenocarcinoma cell line, human fibroblasts and human bone-marrow-derived-mesenchymal stem cells with bioinstructive hyaluronan microparticles that mimic the tumor extracellular matrix to improve lung tumor microenvironment modelling. The results showed that the 3D microspheres increased cell viability and self-assemble together with CD44 expression. These 3D cultures were reproducible and presented characteristics of in vivo solid tumors. Moreover, mesenchymal stem cells exhibited human tumor-like behaviour by migrating through the 3D spheres and interacting with cancer cells and fibroblasts. Finally, administration of doxorubicin in cultures with mesenchymal stem cells revealed their cytotoxic responses, showing the critical need of including mesenchymal stem cells and fibroblasts in 3D in vitro lung tumor models. Overall, the researchers provide evidence of the importance of combining different cell types in tumor models and demonstrate that hyaluronan-microparticles can be used as tumor spheroids scaffolds with the potential to combine them with different extracellular matrix components to improve 3D models.
Bioinstructive microparticles for self-assembly of mesenchymal stem cell-3D tumor spheroids
J F Mano, V M Gaspar
Added on: 11-22-2021
In vitro molecular characterization of immune response following infection with a potentially oncolytic virus
2018
Duke University School of Medicine, Durham, USA
Engaging innate antiviral responses is considered key for instigating tumor-antigen-specific antitumor immunity with cancer immunotherapy approaches. The recombinant poliovirus PVSRIPO could be potentially used as cancer therapy. In the present study, the researchers assessed the interaction of PVSRIPO and the innate antiviral response by infecting a panel of human melanoma cell lines and assaying in vitro innate immune signals and viral translation, propagation, and cytotoxicity over time. The results show that provoking an antiviral response in infected tumor cells without abrogating viral cytotoxicity and the presentation of endogenous tumor antigens may be particularly auspicious for PVSRIPO’s capacity for instigating tumor antigen-specific antitumor immunity.
Engineered oncolytic poliovirus PVSRIPO subverts MDA5- dependent innate immune responses in cancer cells
Matthias Gromeier
Added on: 07-29-2021
Nitrosamines in second-hand smoke can induce tumorigenicity
2018
Taipei Medical University, Taipei, Taiwan
Breast cancer is the most prevalent cancer in women worldwide. Despite the lack of solid confirmation, there is some evidence that suggests a direct correlation between the exposure of second-hand smoke and breast cancer risk. Here, a human immortalized non-tumorigenic breast cancer cell line was exposed to nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in time-course assays of 23 cycle-treatments to elucidate the carcinogenesis potential of these nitrosamines. The results showed that co-exposure of second-hand smoke doses of the nitrosamines induced changes in cell features associated with tumorigenicity. Additionally, there was an activation of factors associated with cellular proliferation and survival and cell stemness. Overall, the researchers demonstrate that chronic exposure to low doses of components of second-hand smoke can induce changes in cell physiology that could potentially drive towards tumorigenic behaviour.
Long-term exposure to extremely low-dose of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induce non-malignant breast epithelial cell transformation through activation of the a9-nicotinic acetylcholine receptor-mediated
Yuan-Soon Ho
Added on: 10-13-2021
Semi-open breathing alveolar lung-on-a-chip
Company 2018
AleveoliX, Bern, Switzerland
Primary human pulmonary alveolar cells (hAEpCs) and primary pulmonary endothelial cells are cultivated in the system. They are applied to both sides of a thin, flexible membrane to create a bioartificial, flexible alveolar barrier. A cyclical negative pressure is generated in the cavity located below the micro-membrane. This simulated breathing is important because it influences the permeability of the epithelial barrier. It offers easy sampling and high throughput and is also compatible with a number of standard readout techniques including ELISA, transepithelial electrical resistance (TEER), permeability testing, qPCR, immune staining and electron microscopy. It is ideal for general lung research, basic research on pulmonary alveoli, preclinical testing of new drugs and can ultimately enable patient-specific precision medicine.
Medium throughput breathing human primary cell alveolus-on-chip model
www.alveolix.com
Added on: 05-25-2020
Study on correlation of biomarkers with squamous cell lung carcinoma
2018
University of Colorado Denver, Aurora, USA
Immunotherapy against marker PD-L1 has demonstrated success in the treatment of advanced non-small-cell lung cancer. However, few analyses exist on the adequacy of such treatment in early-stage squamous cell lung carcinoma (SqCLC). In this study, the researchers evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC patients. The researchers found that the studied biomarkers were independent of each other and none was associated with overall survival.
Correlation of PD-L1 expression with tumor mutation burden and gene signatures for prognosis in early-stage squamous cell lung carcinoma
Fred R. Hirsch
Added on: 07-27-2021
α1-antitrypsin regulates metastasis in triple-negative breast cancer
2018
The Second Affiliate Hospital of Kunming Medical University, Kunming, China
α1-antitrypsin is highly expressed in several types of cancer but its role in triple-negative breast cancer remains unknown. Here, human tissue from triple-negative breast cancer patients and cancerous and non-cancerous human breast cell lines were used to study the influence of α1-antitrypsin in cell migration and invasion and its molecular mechanisms in triple-negative breast cancer cells. The results showed that α1-antitrypsin is overexpressed in triple-negative breast cancer samples and correlated with tumor progression. Moreover, the silencing of α1-antitrypsin in cancer cells inhibited cell growth and migration at the same time that upregulated E-cadherin and tissue inhibitor of metalloproteinases 2. On the contrary, it downregulated other factors positively related to cell invasion and metastasis. Finally, the signalling pathway related to metastasis that activates α1-antitrypsin was identified. Overall, the researchers demonstrate that α1-antitrypsin has high levels of expression in triple-negative breast cancer tissue and that it has a positive regulatory role in metastasis, making it a potential target for new therapeutic strategies in triple-negative breast cancer.
Silence of α1-antitrypsin inhibits migration and proliferation of triple negative breast cancer cells
Yi Zhang
Added on: 11-01-2021
3D model of hypoxia in tumor microenvironment
2018
University of Nebraska Medical Center, Omaha, USA(1)
University of Nebraska-Lincoln, Lincoln, USA(2)
University of Nebraska-Lincoln, Lincoln, USA(2)
A hydrogel-based 3D model is developed to study hypoxia in epithelial to mesenchymal transition in human breast cancer cells. This model shows the importance of hypoxia as a trigger of epithelial to mesenchymal transition and cancer cell migration. When combining human breast cancer hydrogels with lung mesenchymal cells hydrogels, in hypoxic conditions, the researchers confirmed the activation of invasive behaviour of cancer cells. Also, it was possible to identify a new potential target to block cancer cell invasion with the same model. Overall, this study validates these new hydrogel-based 3D models as tools to study metastasis-related mechanisms.
3D hydrogel breast cancer models for studying the effects of hypoxia on epithelial to mesenchymal transition
Vimla Band(1), Bin Duan(2)
Added on: 07-21-2021
3D scaffols for cancer modelling
2018
University of Padova, Padova, Italy
Electroporation is a common technique usually applied to suspension or monolayer cultures. However, 3D systems better reproduce the complex in vivo conditions and cell-matrix interactions. Recent studies have applied electroporation to 3D models replicating in vivo conditions, but still with important limitations. Here, a 3D macroscopic myxoid matrix scaffold to culture human breast epithelial cancer cells was developed to mimic myxoid stroma tumours and replicate the cell-cell and cell-matrix interactions existing in vivo. The results showed that the newly developed platform induced cell proliferation and allows the construction of cell-produced fibrous structures that correlate positively with culture time. Moreover, this system allowed to efficiently electroporate cells cultured on the scaffold. Overall, the researchers propose a new culture system that reproduces key features of in vivo myxoid stroma tumours and can be used to investigate the applicability of electrochemotherapy in cancer.
Cell-seeded 3D scaffolds as in vitro models for electroporation
Elisabetta Sieni
Added on: 11-02-2021
Activity-dependent distribution of S6K1 in a cancer 3D model
2018
National Academy of Sciences of Ukraine, Kyiv, Ukraine
A spheroid model with a human breast adenocarcinoma cell line was used to study the importance of motility in the subcellular localization of the ribosomal protein S6K1. When in dense 2D cultures, S6K1 was localized in the cytoplasm, while it was translocated into the nucleus during migration assays. Meanwhile, in human samples, this protein was localized in the nucleus in cancerous tissues but in the cytoplasm in healthy controls. This study shows the dynamic possibilities that the combination of human samples and "in vitro" 3D models can bring to deciphering the mechanisms that drive cancer cells behaviour.
Nucleocytoplasmic distribution of S6K1 depends on the density and motility of MCF-7 cells in vitro
Antonina Khoruzhenko
Added on: 08-02-2021
Bioprinted 3D breast cancer tumor formations
2018
University of Waikato, Waikato, New Zealand
Bioprinted 3D tumor formations are being developed for the study of breast cancer and personalized drug screening.
Bioprinted 3D tumor formations are in the works
Shalini Guleria
Added on: 05-25-2020
Colorectal cancer immune profiling in Lynch syndrome patients
2018
University of Texas MD Anderson Cancer Center, Houston, USA
In the present study, the researchers aimed at characterizing the immune profile, mutational rate, and neoantigen formation of premalignant lesions in patients with Lynch syndrome (LS). The researchers used whole-genome transcriptomic analysis of data from patients and showed that LS polyps have a distinct immune profile and antigen repertoire that opens the door to the implementation of vaccines or immune checkpoint inhibitors for cancer prevention in premalignant lesions.
Immune profiling of premalignant lesions in patients with Lynch syndrome
Eduardo Vilar
Added on: 07-27-2021
Epitope mapping for immunotherapy against cancer caused by papillomavirus
2018
Arizona State University, Tempe, USA
An increasing number of head and neck squamous cell carcinomas (HNSCC) is caused by human papillomavirus subtype 16 (HPV16). In the present study, the researchers used an in silico approach to predict immunogenic HPV16 T-cell epitopes as potential tools to activate immune cells against HPV+ cancer cells. The researchers then used a combination of analysis using transcriptomics of cancer cells and pulsing of immune cells to demonstrate that T cell dysfunction in patients could be reversed using targeted activation and expansion of T cells using HPV epitopes in combination with checkpoint blockade drugs. These results have implications for the development of immunotherapies for HNSCC caused by HPV.
Human papilloma virus specific immunogenicity and dysfunction of CD8+ T cells in head and neck cancer
Karen S. Anderson
Added on: 09-13-2021
Ex-vivo 3D model for personalized medicine in breast cancer
2018
Universita degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
Taselisib and ipatasertib are two inhibitors of the PI3K and AKT pathways, respectively, currently tested in clinical trials. Previous studies have shown that they have efficient anti-tumor activity when combined with anti-microtubule drugs in human breast cancer cell lines. Here, to better profile the treatment strategy with these inhibitors, a new ex-vivo 3D culture with human breast cancer samples is developed to identify new biomarkers that can predict treatment efficacy in individual patients. The results show that this model replicates in vitro the clinical features of the original tumors. Through next-generation sequencing, a correlation was found between mutations in PI3KA and the efficacy of the treatment. Moreover, several mutations in genes from other important signalling pathways were also found to induce resistance to the treatment, which would make them candidates as negative predictive factors. Overall, the researchers propose a new ex vivo 3D model that replicates human breast cancer features in vitro and allows to identify genetic markers of resistance and rapid drug screening for personalized medicine.
Three dimensional primary cultures for selecting human breast cancers that are sensitive to the anti-tumor activity of ipatasertib or taselisib in combination with anti-microtubule cytotoxic drugs
Floriana Morgillo, Michele Orditura
Added on: 10-03-2021
In silico model to identify specific cancer epitopes
2018
Broad Institute of MIT and Harvard, Cambridge, USA
The study presents an in silico approach build on cancer patients omics to identifying specific epitopes only expressed in cancer cells. This approach should be considered for prospective personalized cancer vaccine development.
Intron retention is a source of neoepitopes in cancer
Eliezer M. Van Allen
Added on: 07-06-2021
Intratumor heterogeneity is a key factor in cancer treatment
2018
Oslo University Hospital Radiumhospitalet, Oslo, Norway
Despite the advances in HER2+ breast cancer treatments and the improvements in survival rates, relapse still remains a fatal complication. Recently, several studies have suggested intratumor heterogeneity of estrogen receptor and HER2 expression to be a critical factor in treatment failure. However, how this evolves at a single-cell level is still unclear. Here, samples from patients, before and after treatment, were used to analyze estrogen receptor and HER2 expression and HER2 gene copy numbers in single tumor cells. The results showed high variability and heterogeneity of HER2 copy numbers among different patients. Moreover, intratumor heterogeneity correlated positively with short disease-free survival and fewer long-term survivors. Additionally, those patients to whom HER2 profile remained constant along treatment had a worse prognosis. Overall, the researchers confirm in human samples the central role of intratumor heterogeneity in cancer progression and remark the importance of treatment selection in HER2+ breast cancer patients.
Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors
Hege G Russnes
Added on: 10-21-2021
Microfluidic system to model cancer cell migration through blood vessels
2018
University of Cambridge, Cambridge, United Kingdom
To model cancer cell transendothelial migration, the researchers develop a microfluidic-chip system where they seed endothelial cells supported on extracellular matrix to mimic a microvessel environment. This system is coupled to live-cell imaging that can be used to study the migration dynamics in 3D. Thanks to this model, some key insights into the mechanisms of cancer cell migration are suggested, showing the potential of this model in cancer and microvascular research.
Image-assisted microvessel-on-a-chip platform for studying cancer cell transendothelial migration dynamics
Yan Yan Shery Huang
Added on: 07-14-2021
Multiphase and multicellular 3D model of breast cancer metastasis to bone
2018
Max Bergmann Center of Biomaterials, Dresden, Germany
The study describes the development of a 3D model based on hydro- and cryogels containing human breast cancer cells and human primary osteoblasts, respectively. The properties of the gels can be tuned to manipulate cell function, which allows the modulation of cellular migration. All these possibilities corroborate the potential of these models to create biomimetic microenvironments to investigate cell-cell and cell-matrix interactions in metastatic processes.
Three-dimensional in vitro hydro- and cryogel-based cell-culture models for the study of breast-cancer metastasis to bone
Laura J Bray
Added on: 07-22-2021
Nanoparticle-based therapy for anti-tumour treatments
2018
Queen’s University, Kingston, Canada(1)
Royal Military College of Canada, Kingston, Canada(2)
Royal Military College of Canada, Kingston, Canada(2)
Smart drugs for cancer therapy have been a popular topic in recent years. However, the limitations of current 2D in vitro models to test these drugs have been a severe constraint in the development of safer and more efficient therapeutic agents. Nevertheless, 3D models have been shown to be a potentially valid alternative to increase the translationality of cancer research. Here, a functionalised nanoparticle is tested to target and penetrate in the inner core of an in vitro 3D multicellular tumour spheroid with human pancreatic and breast cancer cells to deliver cancer drugs. The results show that the nanoparticles could efficiently transport and release the hydrophobic drugs into the tumour spheroid core. Furthermore, this treatment induced a significant reduction of the spheroid's volume that was dose- and time-dependent. Overall, the researchers develop and describe a functionalised nanoparticle that can internalise and deliver hydrophobic drugs in the inner core of tumour spheroids, opening the door to more efficient cancer therapies.
Functionalized folic acid-conjugated amphiphilic alternating copolymer actively targets 3D multicellular tumour spheroids and delivers the hydrophobic drug to the inner core
Myron R Szewczuk(1), Cecile Malardier-Jugroot(2)
Added on: 10-18-2021
Spheroids to study cancer stem cells
2018
Ankara University, Ankara, Turkey
Cancer stem cells have become a popular subject of study. To better understand their properties, it is necessary to improve the current in vitro models. Here, a 3D in vitro system is used to analyse the cancer stemness of a human breast cancer cell line and a human glioblastoma cell line. The results showed that breast cancer cells were able to form uniform 3D structures and acquired cell stem cell features. Targeting cancer stem cells with metformin reduced the expression of genes related to drug resistance. Furthermore, it also increased the effectiveness of 5-fluorouracil. Overall, the researchers demonstrate that the use of 3D models in vitro can improve the translationality of cancer models, as they help replicate tumour microenvironments and have diverse cellular populations as it occurs in vivo.
Evaluation of cancer stemness in breast cancer and glioblastoma spheroids in vitro
Açelya Yilmazer
Added on: 10-18-2021
3D model to study drug resistance in cancer
2018
Dalian Medical University, Dalian, China
Multidrug resistance is a very important limitation of chemotherapy that hinders the efficiency of current treatments. However, there is not enough data generated that can be useful to understand and overcome this complication due to the complexity of recapitulating drug-resistant cancer cells behaviour in vitro. Here, a 3D model is developed culturing adriamycin-resistant human breast cancer cells in silk-collagen scaffolds to better replicate in vivo features. The results showed that breast cancer cells behaved differently in 2D versus 3D cultures, involving cancer and drug resistance-related mechanisms. Additionally, cancer cells were more resistant to drugs in the 3D culture through increased drug efflux capability. Moreover, cells presented an altered cell cycle distribution and there was an increased proportion of breast cancer stem cells, which might have a critical role in the development of drug resistance in tumours. Overall, the researchers develop a robust 3D model that better replicates drug-resistant cancer cell behaviour, which may allow to better investigate the mechanisms underlying the development of cancer drug resistance and further improve chemotherapeutic strategies.
Three-dimensional tissue culture model of human breast cancer for the evaluation of multidrug resistance
Xiuli Wang
Yanfang Ding et al. Journal of Tissue Engineering and Regenerative Medicine 2018 [402]
EURL ECVAM [403]
Added on: 10-26-2021
Bioinformatics to design breast cancer therapy
2018
Tabriz University of Medical Sciences, Tabriz, Iran
Triple-negative breast cancer (TNBC) is an important subtype of breast cancer. TNBC may be a cancer testis antigen (CTA)-positive tumor, opening the door for therapy targeting the CTA. In the present study, the researchers used an immunoinformatics approach to design a peptide vaccine to combat TNBC using three peptides in order to stimulate the humoral, cellular and innate immune responses. The vaccine structure was also subjected to the molecular dynamics simulation study for structure refinement. The informatics results verified the immunogenicity and safety profile of the constructed vaccine as well as its capability for stimulating both the cellular and humoral immune responses. The proposed vaccine may be considered for the immunotherapy of TNBC.
In silico design of a triple-negative breast cancer vaccine by targeting cancer testis antigens
Yadollah Omidi
Added on: 07-27-2021
In silico 3D model of solid tumors to screen for optimal immunotherapy
2018
University Medical Center Heidelberg, Heidelberg, Germany
Most solid tumors in cancer are resistant to immunotherapy because of the immunosuppressive effect of the tumor microenvironment. In the present study, the researchers developed an in silico 3D model of human solid tumor tissue that can comprise over a million cells, including the different categories of cells usually present in solid tumors, and over clinically relevant timeframes. This model could be informed by individual patient data to generate individual in silico tumor explants. The stratification of growth kinetics of these explants could reasonably predict survival in a cohort of patients. Further, the model was used to simulate the effect of chemotherapy, immunotherapies, and cell migration inhibitors alone and in combination to try to find optimal treatment strategies. This platform can complement other patient-specific ex vivo models and can be used for high-throughput screening of combinatorial immunotherapies.
High-throughput screening of combinatorial immunotherapies with patient-specific in silico models of metastatic colorectal cancer
Jakob Nikolas Kather, Niels Halama
Added on: 09-13-2021
Label-free and real time monitoring of cell viability in 3D tumour spheroids
2018
The University of Edinburgh, Edinburgh, United Kingdom
Here an electrical impedance tomography is used to measure cell viability in a 3D model of tumour spheroids that allows them to do label-free monitoring of drug testing. They demonstrate both "in vivo" and "in silico" that their method works. With this method they could measure in real time the loss of cell viability in a 3D model of breast cancer.
Electrical impedance tomography for real-time and label-free cellular viability assays of 3D tumour spheroids
Jiabin Jia
Added on: 07-02-2021
3D chip tumor model for high-throughput drug efficacy evaluation
2018
Tsinghua University, Shenzhen, China
A cancer-on-chip device with a vascular-like system and multicellular tumor spheroids was used to evaluate therapeutic nanoparticle-based drug delivery. The model allows for the evaluation of dynamic transport and cytotoxicity at the same time. In this model, it was possible to observe the differences in the efficacy of different therapeutic strategies in different human breast cancer subtypes, both at the level of penetrance and cytotoxicity. Overall, this model allows for high-throughput analysis of several aspects involved in drug efficacy in a 3D tumor microenvironment.
A novel 3D breast-cancer-on-chip platform for therapeutic evaluation of drug delivery systems
Dan Gao
Added on: 08-02-2021
Blood vessels-on-a-chip displays substance exchange and reaction to growth factors
2018
Technische Universität Wien Institut für Angewandte Synthesechemie, Vienna, Austria
Organ-on-a-chip-systems can be used to precisely control, monitor and measure complicated biological processes - much better than would be possible directly on humans.
Endothelial cells are used and stem cells are added in order to contribute to vascular stabilisation. Based on these cells, a network of small blood vessels is built within a few days. These are supplied with oxygen and nutrients via an artificial artery - without direct connection, but substance exchange is possible. This plays an important role in wound healing as well as in diseases like cancer. A fast-growing tumour must be able to be supplied with sufficient quantities of nutrients - which is why it ensures unnaturally fast growth of fine blood capillaries. The chip can now be used to investigate the exact process of nutrients transfer much better than it was possible to date.
Engineering of three-dimensional pre-vascular networks within fibrin hydrogel constructs by microfluidic control over reciprocal cell signaling
Peter Ertl
Barbara Bachmann et al. Biomicrofluidics 2018 [412]
innovations report: Forum für Wissenschaft, Industrie und Wirtschaft [413]
Added on: 04-30-2020
Computerized testing of breast tissue characterization imaging techniques
2018
Federal University of Technology - Paraná, Curitiba, Brazil
A combination of x-ray fluorescence and scattering spectroscopy is applied to characterise breast tissues. These techniques were tested with a Monte Carlo computational study. The results show that this combination is able to produce images to map breast tissue samples and they can be complementary for breast tissue characterisation.
Characterization of breast tissues combining x-ray fluorescence and scattering spectroscopy: a Monte Carlo computational study
Marcelo Antoniassi
Added on: 07-30-2021
Cytological cell blocks for drug screening in advanced lung cancer
2018
Jewish General Hospital, Montreal, Canada
Immunohistochemical analysis (ICH) of the tumor surface protein PD-L1 ("programmed death ligand 1") is of high clinical relevance for the selection of a suitable therapeutic agent in non-small-cell lung cancer (NSCLC). Tumor cells that express PD-L1 are not recognized by the T cells of the body's immune system and elude defence reactions. Clinical studies show that treatment with so-called checkpoint inhibitors, such as pembrolizumab, can strengthen the immune response to the cancer cells again. For a PD-L1-ICH, tumor tissue samples are obtained by small needle biopsies or surgical resection as standard. These invasive procedures are unsuitable for frail patients in the advanced stage and lead to their exclusion from relevant drug studies. In the present study, the PD-L1-ICH of cytological cell blocks was evaluated in several test series and compared with immunohistochemical analyses of small biopsies and surgical tissue samples of the same patients. Based on the Tumor Proportion Score (TPS), the samples were divided into three PD-L1 expression groups (negative, low, and high). Of particular interest was the patient group that was at an advanced stage of NSCLC (high TPS ≥50%), as high expressions are associated with a good response to treatment with checkpoint inhibitors and are associated with higher survival rates. Furthermore, factors such as the type and age of the samples were taken into account in the investigations. Most of the cytological cell blocks were comparable to the small biopsy samples and suitable for PD-L1 testing. PD-L1 expression, as well as the presence of certain predictive biomarkers, was evaluated using statistical methods. Based on the results, the research group evaluates the PD-L1-ICH cytological cell blocks as a suitable and valuable method for the integration of previously unconsidered patient groups into clinical lung cancer studies.
Cytology cell blocks are suitable for immunohistochemical testing for PD-L1 in lung cancer
Hangjun Wang
Added on: 09-08-2022
Immunodetection of breast cancer antigen in biological samples
2018
Tabriz University of Medical Sciences, Tabriz, Iran
The study describes the development of an ultrasensitive electrochemical immunosensor to detect Carcinoma Antigen 15-3 in biological samples. The sensor is able to reliably detect the antigen in human breast adenocarcinoma cell lysates and in untreated human plasma from patients. This device can be a powerful tool to improve the detection and prognosis of human breast cancer.
Immunosensing of breast cancer prognostic marker in adenocarcinoma cell lysates and unprocessed human plasma samples using gold nanostructure coated on organic substrate
Mohammad Hasanzadeh
Mohammad Hasanzadeh et al. International Journal of Biological Macromolecules 2018 [417]
EURL ECVAM [418]
Added on: 07-27-2021
In silico model of anti-cancer target to improve drug design
2018
Zhengzhou University, Zhengzhou, China
Human PD-1 (hPD-1) is a transmembrane immunoglobulin that interacts with its ligands PD-L1 to prevent excessive T cell activation and maintain self-tissue tolerance. Cancer treatment by modulating the PD-1/PD-L1 axis has been highly promoted since PD-L1 was reported to be over-expressed in a wide variety of solid tumors which evade immune surveillance. In the present study, the researchers sought to better understand the functionality of the PD-1 molecule and its ligand, PD-L1, using detailed 3D structures and their interactions using in silico molecular dynamics simulations. Based on predictions, the researchers were able to design ligands with improved binding capacity and confirmed the results in vitro. This in silico model should be used as a tool to facilitate rational drug design of molecules that can modulate PD-1’s pathways.
The design of high affinity human PD-1 mutants by using molecular dynamics simulations (MD)
Yanfeng Gao
Added on: 09-15-2021
Machine learning method for breast cancer diagnostics
2018
Radboud University Medical Center, Nijmegen, Netherlands
This method is based on machine learning techniques to gain insights into stromal changes associated with breast cancer. Using deep convolutional neural networks, the algorithm was trained to discriminate between invasive breast cancer-related stroma from benign biopsies from patients. Afterwards, the algorithm could perform correctly and even could be used to detect ductal carcinoma. These results show that algorithms can be powerful tools to classify breast biopsies and understand breast insults.
Using deep convolutional neural networks to identify and classify tumor-associated stroma in diagnostic breast biopsies
Jeroen A W M van der Laak
Added on: 07-22-2021
MMP2 modulates cell invasion in breast cancer cells
2018
Indian Association for the Cultivation of Science, Kolkata, India
Tumor cells are thought to secrete matrix metalloproteinases that degrade the extracellular matrix, promoting cell invasion. Some of these mechanisms have been elucidated in the last years, however, the role of TF-FVIIa/trypsin activation of protease-activated receptor 2 driving MMP2 upregulation in cell invasion is still unclear. Here, human breast cancer cells were used to study the different signalling mechanisms on the protease-activated receptor 2 mediated MMP2 increased expression that affect cell migration. The results showed that the knockdown of protease-activated receptor 2 hindered the upregulation of MMP2. Similarly, the knockdown of MMP2, impeded TF-FVIIa/trypsin-induced cell invasion. Moreover, the protease-activated receptor 2 driven upregulation of MMP2 was identified to lean on the PI3K-AKT-NF-ĸB pathway. Furthermore, TF, protease-activated receptor 2 and MMP2 were found to be overexpressed in invasive breast carcinoma tissues. Finally, the signalling axis triggered by MMP2 that modulates actin polymerization and cell migration was identified, which could be pharmacologically attenuated. Overall, the researchers describe the signalling pathway through which protease-activated receptor 2-induced MMP2 expression regulates cell invasion in breast cancer cells, which can help future developments of new therapeutical strategies to block metastatic processes.
Matrix metalloproteinase-2: A key regulator in coagulation proteases mediated human breast cancer progression through autocrine signaling
Prosenjit Sen
Added on: 10-30-2021
New assay to predict patient response to immunotherapy
2018
Johns Hopkins University School of Medicine, Baltimore, USA
Patients can mount endogenous immune responses against mutation-associated neoantigens (MANA), but these responses are countered by immunosuppressive signals—so-called checkpoints. Unleashing of MANA-specific T cells by checkpoint blockade promotes tumor regression in patients. In the present study, the researchers develop an assay called MANAFEST to identify MANA-specific immune response in tumor tissue and in the blood by checkpoint blockade. This assay has great sensitivity, specificity and high-throughput capacity and could be used as a pan-cancer predictor of response to immunotherapy.
The mutation-associated neoantigen functional expansion of specific T cells (MANAFEST) assay: a sensitive platform for monitoring antitumor immunity
Kellie N. Smith
Added on: 07-26-2021
Proteomics in a 3D bioprinted placenta
2018
Center for Engineering Complex Tissues, University of Maryland, College Park, USA
The placental basement membrane (BM) proteins (e.g. laminin, collagen) has been implicated in the development of placenta while the level of laminin is significantly lower in preeclampsia. The authors hypothesized that placental BM proteins are required for effective cytotrophoblast invasion. Using proteomics, the study finds that more than 80% of ECM (extracellular matrix) proteins in placental basal plate were BM proteins. Thus, the ECM microenvironment substantially regulates cytotrophoblast invasion, an area that is less investigated but appears to be critical in the pathogenesis of preeclampsia. Moreover, this model can be an attractive option to screen and develop novel therapeutics and biomarkers not only in preeclampsia but also other diseases such as cancer metastasis.
Placental basement membrane proteins are required for effective cytotrophoblast invasion in a 3d bioprinted placenta model
John P. Fisher
Added on: 07-09-2020
Testing the capacity of oncolytic virus to treat brain cancers in patients tissue
2018
Duke University Medical Center, Durham, USA
Pediatric brain tumors could potentially be treated by poliovirus oncolytic immunotherapy. In the present study, the researchers analysed low-grade and malignant pediatric brain tumors infected with recombinant polio: rhinovirus (PVSRIPO) and determined the expression of the poliovirus receptor as proof of infection and propagation. Also, the capacity of the infection to lower cancer cell proliferation was shown in vitro. Given a similar successful translation of PVSRIPO to treat malignant gliomas in adult and pediatric patients, future work and prospective clinical trials should explore this possibility of PVSRIPO as an immunotherapeutic approach to treating pediatric brain tumors.
Poliovirus receptor (CD155) expression in pediatric brain tumors mediates oncolysis of medulloblastoma and pleomorphic xanthoastrocytoma
Eric M. Thompson
Eric M. Thompson et al. Journal of Neuropathology & Experimental Neurology 2018 [428]
EURL ECVAM [429]
Added on: 07-29-2021
3D spheroids screening for cancer drugs identification
2018
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, USA
The study implements a high throughput screening approach using 3D spheroids for the identification of signaling targets in oncology. The authors identify Proscillaridin A as a selective inhibitor of cells harboring a specific oncogenic allele.
A novel three-dimensional high-throughput screening approach identifies inducers of a mutant KRAS selective lethal phenotype
Joseph Kissil, Timothy Spicer
Added on: 04-21-2020
Bioreactor model for drug efficacy studies
2018
University of Florida, Orlando, USA
Nowadays, HER2+ resistant breast cancer is a major clinical challenge. Several studies have shown some of the pathways that are responsible for the acquisition of resistance of this type of tumors, which can be targeted with different already available drugs. Here, a classic 2D and a novel bioreactor-based 3D models are developed to study a triple combination therapy that targets the known pathways responsible for chemotherapy resistance in human breast cancer cells. The results show that treatment with paclitaxel, everolimus and dasatinib induced cell apoptosis in 2D conditions and in the bioreactor 3D dynamic model. With these results, a pharmacokinetics/dynamics mathematical model was generated to correlate the exposure to the novel combinational therapy and its anti-cancer effects. In this study, the researchers demonstrate the utility of a bioreactor-based 3D dynamic model to perform drug screening in an in vitro set-up that replicates in vivo conditions and demonstrate the efficacy of a novel combination therapy that can overcome HER2+ induced drug resistance.
Utility of a novel three-dimensional and dynamic (3DD) cell culture system for PK/PD studies: evaluation of a triple combination therapy at overcoming anti-HER2 treatment resistance in breast cancer
Sihem Ait-Oudhia
Added on: 10-09-2021
Breast fibroblasts induce breast cancer stem cell transformation
2018
Capital Medical University, Beijing, China
Breast cancer stem cells have an important role in metastasis and, recently, it has been shown that they have different phenotypes in different tumour areas at different stages of cancer progression. Cancer-associated fibroblasts have been described to induce epithelial-to-mesenchymal transition, thus promoting cancer stem cell features and their phenotypical transformation. However, the role of normal fibroblasts in breast cancer stem cell behaviour remains unknown. Here, cancer-associated and normal fibroblasts from patients were analyzed and used to test the effects of their paracrine activity on breast cancer stem cells. The results showed that there are no major morphological differences among both types of fibroblasts, but they have different proteomic profiles and cell invasion capacities. Furthermore, cancer-associated fibroblasts conditioned media was more efficient in promoting mammosphere formation than that of normal fibroblasts and both media generated different marker phenotypes of breast cancer stem cells. Overall, the researchers confirmed the differences among cancer-associated and normal fibroblasts and further elucidated their ability to generate different phenotypes of breast cancer stem cells.
Breast fibroblasts in both cancer and normal tissues induce phenotypic transformation of breast cancer stem cells: a preliminary study
Hua Kang
Added on: 10-27-2021
Comparison of invasive breast cancer prediction models
2018
University of Cambridge, Cambridge, United Kingdom
The purpose of this study is to compare two widely used invasive breast cancer prediction models: PREDICT and CancerMath, together with respective improvements, adding a new algorithm in the predictors. The results show that PREDICT performs better and that it is already a robust prediction model in which the addition of new predictor algorithms does not significantly improve its efficacy. In conclusion, PREDICT offers better clinical utility and is already robust enough.
Development and external validation of prediction models for 10-year survival of invasive breast cancer. Comparison with PREDICT and CancerMath
Solon Karapanagiotis
Added on: 07-29-2021
Development of a vascularized microfluidic 3D model of metastasis
2018
Kyoto University, Kyoto, Japan
A multicellular microfluidic, similar to a chip-based device, 3D tumor model that contains a vascular network is described. This new model allows to study the vascular transport of nutrients and cells in the context of interactions between tumor microenvironments and spheroids of other organs and can be potentially used for drug testing.
Vascularized 3D cell constructs to model cellular interactions through a vascular network
Yu-suke Torisawa
Added on: 07-02-2021
Ex vivo testing of the role of lymphatic vessel density in immune response in cancer patients tissues
2018
Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland(1)
University of Lausanne (UNIL), Lausanne, Switzerland(2)
University of Lausanne (UNIL), Lausanne, Switzerland(2)
Poor patient survival in melanoma and other cancers correlates with increased density of tumor-associated lymphatic vessels. Still, lymphatic drainage is essential for initiating an immune response. In the present study, the researchers assessed whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes from patients with cutaneous melanoma. The researchers used immunohistochemistry and quantitative image analysis on patients tissues and found significant positive correlations between LVD and immune cell infiltration as well as expression of the immunosuppressive molecules. Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating regional effects of tumors. The results suggest that lymphatic vessels play multiple roles at tumor sites.
Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma
Melody A. Swartz(1), Daniel E. Speiser(2)
Added on: 07-29-2021
In silico prediction of lung cancer antigen 3D structure to facilitate treatment design
2018
Armed Forces College of Medicine, Cairo, Egypt
XAGE-1b is an overexpressed surface antigen in lung adenocarcinoma and was shown to be strongly immunogenic. The quest for designing immunotherapies as peptide vaccines based on XAGE-1b has been challenged by the lack of detailed structural information regarding its immunogenic properties. In this study, the researchers used a homology modelling technique and performed computer-based 3-dimensional structure models of XAGE-1b. The obtained 3D structure could explain its antigenic function and facilitate the usage of predicted peptides for experimental validation towards designing immunotherapies against lung adenocarcinoma.
Computational prediction of vaccine potential epitopes and 3-dimensional structure of XAGE-1b for non-small cell lung cancer immunotherapy
Mohammad M. Tarek
Added on: 07-27-2021
In vitro analysis of natural killer cells from colorectal cancer at the molecular and cellular level
2018
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
In patients with solid malignancies, NK cells have compromised functions. In the present study, the researchers studied NK cells at a molecular and cellular level from blood and tissue samples of patients with colorectal cancer (CRC) and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC NK cells showed decreased expression of activation marker and impaired degranulation activity. Further, NK cells in CRC secreted pro-angiogenic factors and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro.
Angiogenin and the MMP9–TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer
Douglas M. Noonan
Added on: 07-29-2021
Microvascular chips for the characterization of cardiovascular diseases
2018
Central China Normal University, Wuhan, China(1)
Wuhan Polytechnic University, Wuhan, China(2)
Wuhan Polytechnic University, Wuhan, China(2)
Endothelial cells seeded in hydrogel can form perfusable microvasculature networks by a vasculogenesis-like process. This approach can be used to develop advanced in vitro models where the interactions between functional vasculature (characterized by mature vessel walls and tissue parenchyma) is critical to mimic pathophysiological processes (intra- and extravasation processes involving leukocytes and cancer cells). Diffusion and effects of therapeutics can be tested in complex microenvironments. The device allows the delivery of nutrients, and oxygen, as well as flow-induced mechanical stimuli into the luminal space of the endothelium.
Fine particulate matter (FPM) for example has been thought to be associated with cardiovascular disease. FPMs were introduced into this physiologically human vessel-like microenvironment. The vascular toxicity was evaluated and the results demonstrated that intravascular accumulation of FPM could enhance ROS (reactive oxygen species) generation which may further cause endothelial dysfunction by oxidative stress. This is associated with endothelial inflammation and thrombosis. This simple and versatile platform can be used for a wide range of applications in vascular physiology studies of particulate matter in the context of cardiovascular disease.
Functional human 3D microvascular networks on a chip to study the procoagulant effects of ambient fine particulate matter
Xu Yang(1), Yang Wu(2)
Added on: 07-09-2020
Tunable hydrogel-based extracellular matrix for 3D culture
2018
University of Birmingham, Birmingham, United Kingdom
To try to understand cell dynamics in tumor microenvironments, a tunable hydrogel-based 3D culture system to grow human cancer cell lines is developed. By controlling the mechanical properties of the hydrogels and incorporating different cell adhesion peptides, encapsulated cells show higher cell viability than in other models and participate in processes of extracellular matrix degradation to induce cell proliferation and cluster formation. This model can bring new possibilities to the study of cellular interactions and dynamics within the extracellular matrix.
Design of synthetic extracellular matrices for probing breast cancer cell growth using robust cyctocompatible nucleophilic thiol-yne addition chemistry
Andrew P Dove
Added on: 07-30-2021
A multicellular system to explore metastasis
2018
University of Pittsburgh, Pittsburgh, USA
An ex-vivo model based on a 3D chip microphysiological system mixing human liver samples with human breast cancer cells is used to study spontaneous dormancy of breast cancer cells suggested to be responsible for metastatic processes. The researchers could reproduce this "dormant" behaviour in their model and induce a proliferative state after diverse activation signals. With this system, they could explore relevant features of this type of cells, showing that this model can be used for biomarker research.
A model of dormant-emergent metastatic breast cancer progression enabling exploration of biomarker signatures
Alan Wells
Added on: 07-29-2021
A novel 3D cancer model to test potential immune therapy in a high-throughput fashion
Company 2018
Corning Incorporated, Kennebunk, USA
New cancer models are needed to efficiently screen for potential therapies, especially the promising autologous immune cells. Immune cell therapy has to be tested for its ability to migrate, invade tumors and kill cancer cells. The regular two-dimensional in vitro models based on a monolayer of cultured cells are too limited. The study establishes a more in-vivo-like model combining a 96-well low-attachment microplate and a 96-well permeable support system with standard human cancer cells to form spheroids. This method allows for the investigation of immune cell homing, immune invasion of tumor spheroids, and spheroid cytotoxicity in a high-throughput fashion.
A novel three-dimensional immune oncology model for high-throughput testing of tumoricidal activity
Ann E. Rossi
Added on: 07-06-2021
Development of a microfluidic device for drug screening for Raman measurements
2018
Utah State University, Logan, USA
In recent years, Raman spectroscopy has gained importance in cell classification. However, it is still difficult to apply it to cells cultured in microfluidic devices based on PDMS due to the background noise generated by this material. Here, a novel microfluidic device is used to culture human lung and breast cancer cells to perform Raman spectroscopy and study their response to doxorubicin. The results showed that the new device was biocompatible with the cancer cell lines and that their biomechanical properties were not altered. Furthermore, doxorubicin induced significant changes between treated and untreated cells in the Raman spectroscopy profiles, as reflected by the clustering in principal component analysis. Overall, the researchers develop a new microfluidic device that can be used for in vitro Raman measurements of living cells to investigate drug response and fast drug screening.
Microfluidic chip for non-invasive analysis of tumor cells interaction with anti-cancer drug doxorubicin by AFM and Raman spectroscopy
Anhong Zhou
Added on: 11-02-2021
Immunosensor for CA 15-3 antigen detection in cancer
2018
Tabriz University of Medical Sciences, Tabriz, Iran
A highly sensitive immunosensor is developed to detect the cancer-specific carbohydrate 15-3. The immunosensor showed to be highly selective and reproducible when used with human plasma samples and also with lysates from a human breast adenocarcinoma cell line. The results show that this immunosensor could be a great detection tool for diagnostic purposes.
An innovative immunosensor for ultrasensitive detection of breast cancer specific carbohydrate (CA 15-3) in unprocessed human plasma and MCF-7 breast cancer cell lysates using gold nanospear electrochemically assembled onto thiolated graphe
Mohammad Hasanzadeh
Mohammad Hasanzadeh et al. International Journal of Biological Macromolecules 2018 [456]
EURL ECVAM [457]
Added on: 08-01-2021
Large-scale machine learning cancer genome analysis for therapeutic target identification
2018
Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
The authors describe and evaluate a combination of transcriptomics and machine-learning approaches to classifying aberrant pathway activity in tumors.This may aid identifying patients who will respond well to a certain anticancer therapy. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Potential biomarkers for choosing cancer treatment are identified.
Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas
Casey S. Greene
Added on: 04-21-2020
Mutation load estimation model as a predictor of the response to cancer immunotherapy
2018
National Yang-Ming University, Taipei, Taiwan
Although the efficacy of immunotherapy has been demonstrated, treatment response differs from patient to patient. One tool to predict an individual patient's responses and improve therapeutic efficiency is the identification of patient's specific point mutations also called the mutation load. As far as now, techniques to identify mutation load have been too expensive and time-consuming to be used in the clinic. In the present study, the researchers have used publically available cancer genomics data to generate mathematical predictive models of mutation load for lung adenocarcinoma based only on 24 genes instead of whole-exome sequencing. The same model can be adapted to predict mutation load for melanoma and colorectal cancer. The estimated mutation load can be used to predict the clinical outcome of cancer immunotherapy with high accuracy. Using this estimation model should reduce the cost and time needed for the assessment of the mutation load and facilitate the obtention of cancer immunotherapy response prediction in the standard clinical setting.
Mutation load estimation model as a predictor of the response to cancer immunotherapy
Yi-Chen Yeh, Yu-Chao Wang
Added on: 07-26-2021
3D cancer model for the analysis of tumor microenvironment
2018
Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain(1)
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, USA(2)
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, USA(2)
The authors developed a 3D co-culture model of lung adenocarcinoma cells and macrophages in an interpenetrating network hydrogel. The study shows that the presence of tumor-associated macrophages and the extracellular matrix (ECM) stiffness jointly contribute to an invasive phenotype and modulate the expression of key epithelial-to-mesenchymal transition (EMT)-related markers. The study demonstrates the utility of in vitro 3D cancer models suitable for interactions analyses in the tumor microenvironment.
Matrix stiffness and tumor-associated macrophages modulate epithelial to mesenchymal transition of human adenocarcinoma cells
Maria de la Fuente(1), David J. Mooney(2)
Added on: 04-21-2020
Culture conditions do not affect DNA methylation in breast cancer cells
2018
Jilin University, Changchun, China
In recent years, epigenetic signatures have been shown to have critical roles in the development of cancer. Here, a human breast cancer cell line was used to investigate the direct correlation between DNA methylation and breast cancer in 2D culture, 3D culture and orthotopic transplantation adhesion substrates. The results of PCA analysis showed that the three conditions were closely related. Moreover, several methylation patterns were common among the three conditions and shared several CpG hypermethylated positions. However, the methylation patterns were more closely related between 2D and 3D culture conditions. Furthermore, a genomic analysis identified that four pathways were remarkably affected without notable differences in the methylation status of their genes in the three culture conditions. Overall, the researchers confirm that there are DNA methylation changes in breast cancer and that it is possible to study those changes in several in vitro culture conditions.
DNA methylation is related to the occurrence of breast cancer and is not affected by culture conditions
Hongjun Li
Added on: 11-01-2021
DNA methylation-based tumor classification
2018
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany, Heidelberg, Germany(1)
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany(2)
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany(2)
A big biobank consisting of patient-derived central nervous system tumor biopsies is being developed and utilized for the establishment of a DNA methylation-based tumor classification (https://www.molecularneuropathology.org/mnp). An integrated online tool allows researchers to upload their methylome data, which is then automatically compared to methylation data of a reference cohort comprising over 2800 neuropathological tumors.
MolecularNeuropathology.org - The platform for next generation neuropathology
Andreas von Deimling(1), Stefan Pfister(2)
Added on: 04-21-2020
Doxycycline has anti-cancer stem cells activity
2018
University of Michigan, Ann Arbor, USA
Cancer stem cells are surging as important targets to prevent drug resistance and metastasis in cancer progression. Several studies have used mitochondria to try to disrupt their viability. Here, human breast cancer cell lines were used to investigate the efficiency of doxycycline inhibition of mitochondrial biogenesis in breast cancer stem cells. The results showed that doxycycline decreased the number of ALDH+ breast cancer stem cells, both in normal and paclitaxel-induced enrichment conditions, and inhibited mammosphere formation of different types of breast cancer cells. Moreover, there were low levels of reactive oxygen species in doxycycline-treated cancer cells and lower activation of their downstream signalling pathway. Consequently, direct inhibition of downstream effectors of doxycycline signalling could replicate the effects of the drug in decreasing the number of ALDH+ breast cancer stem cells. Overall, the researchers report the anti-cancer stem cell activity of an FDA-approved drug that could be used concomitantly with other chemotherapeutic strategies to limit the effects of cancer stem cells.
Doxycycline targets aldehyde dehydrogenase‑positive breast cancer stem cells
Duxin Sun, Miao‑Chia Lo
Added on: 11-01-2021
Immunofluorescence in brain cancer tissues to reveal potential for immune checkpoint inhibitors treatment
2018
Brigham and Women’s Hospital, Boston, USA
Surgical resection of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. In the present study, the researchers explored the feasibility of targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway in craniopharyngiomas. The researchers mapped and quantified PD-L1 and PD-1 expression in patients' resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. Also, they used tissue-based cyclic immunofluorescence to map the spatial distribution of immune cells and characterize cell cycle and signalling pathways in tumor cells that intrinsically express PD-1. All results indicate that targeting PD-L1 and/or PD-1 in craniopharyngioma might be an effective therapeutic strategy.
Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma
Sandro Santagata
Added on: 07-29-2021
In vitro testing of increase of antigen presentation in cancer cells following chemotherapy
2018
University of London, London, United Kingdom
The success of immunotherapies depends on the antigenic makeup of tumour cells. Improving the efficacy of cancer treatments is to augment the antigens displayed by tumours. In the present study, the researchers explored possible alteration of tumour recognition by gemcitabine (GEM), a nucleoside analogue that has a broad spectrum of anti-tumour activity. Testing a panel of chemotherapeutics in human cancer cell lines in vitro, the researchers found that it was found that GEM increased surface expression of a variety of immunogenic antigens. These data may advise as to which antigens should be used in future vaccination protocols and reinforce the idea that chemotherapy and immunotherapy could be used in combination.
Gemcitabine alters the proteasome composition and immunopeptidome of tumour cells
A. M. Gravett
Added on: 07-29-2021
Mathematical and experimental approaches to improve electrochemotherapy treatments
2018
University of Padova, Padua, Italy
Through mathematical modelling of different needle spacing, it is shown that grid electrodes can be improved for electrochemotherapy to improve coverage of the treatment area. After finding the optimal distance and voltage, the researchers confirmed in a model of human breast cancer that these parameters allow for more homogeneous electroporation. Finally, it is confirmed that computational models and experimental procedures can be used to adjust the grid electrode's configuration.
Effect of electrode distance in grid electrode: numerical models and in vitro tests
Elisabetta Sieni
Added on: 07-12-2021
Molecular biology engineering of a molelcule with in vitro antitumor activity
2018
Guangzhou Medical University, Guangzhou, china
Cancer vaccines have been used to both treat and prevent cancer by targeting the immune system. Similar to classic vaccines, most therapeutic cancer vaccines are also made using protein or peptide antigens. Staphylococcal enterotoxins (SEs) are powerful peptide antigens produced by Staphylococcus aureus which trigger a powerful immune response. In the past, SEs were fused to ligands that bind to receptors expressed or overexpressed on the target cells and were named “ligand-targeted therapeutics (LTTs)". Epidermal growth factor (EGF) is the natural ligand that binds to the EGF receptor (EGFR) and activates more than 200 downstream signal molecules to initiate or modulate various intracellular processes. Most nasopharyngeal cancer cell lines and patients overexpress EGFR, which was thus proposed as a new target for cancer treatment. In the present study, the researchers used molecular biology engineering to produce a fusion protein from SE genetically conjugated to EGF forming a chimeric construct. The fusion protein was expressed and purified from bacteria Escherichia coli. Then, the ability of the chimeric molecule to bind to patients cancer cells was determined ex vivo as well as its antitumor effect. The chimeric molecule is the first of its kind to display antitumor activity and should pave the way for further therapy development.
Construction, expression, and characterization of rSEA-EGF and in vitro evaluation of its antitumor activity against nasopharyngeal cancer
Ailin Tao
Added on: 09-14-2021
New approach to achieve homogeneous multicellular tumor spheroids
2018
University of British Columbia, Vancouver, Canada
Different sonication parameters are used to achieve a uniform mixture of gelling agents that allows homogeneous integration of cancer cells to form tumor spheroids. Using breast cancer cells, the authors show that they can manipulate the hydrogel structure with this new protocol without inhibiting cell proliferation in spheroids.
A novel approach to producing uniform 3-D tumor spheroid constructs using ultrasound treatment
Karen C Cheung
Added on: 07-03-2021
New sequencing methods in lung cancer patient' tissue to predict response to immunotherapy
2018
Memorial Sloan Kettering Cancer Center, New York, USA
An urgent need exists to develop clinically practical tools to identify the subset of lung cancer patients most likely to derive clinical benefits from treatment based on immune checkpoint inhibitors (ICIs). In the present study, the researchers hypothesized that determining the tumor mutation burden by targeted Next Generation Sequencing may help predictions. 240 patients with lung cancer and treated with immune checkpoint blockade were profiled by targeted NGS. A subset of tumors from these patients was analyzed by another sequencing method called Whole Exome Sequencing (WES) to strengthen the analysis. The data showed that elevated TMB improved the likelihood of benefit to treatment by immune checkpoint blockade. Interestingly, TMB did not correlate with the expression of main markers for use of immune checkpoint blockade; the incorporation of both variables should be introduced into multivariable predictive models to generate greater predictive power.
Molecular determinants of response to anti–Programmed Cell Death (PD)-1 and anti–Programmed Death-Ligand 1 (PD-L1) blockade in patients with non–small-cell lung cancer profiled with targeted Next-Generation Sequencing
Matthew D. Hellmann
Added on: 09-17-2021
Novel in vitro pancreatic tumor model recapitulates tumor characteristics and microenvironment
2018
Medical College of Wisconsin, Milwaukee, USA
First report of novel and disease-relevant 3D in-vitro models representing pancreatic tumor, stromal and immune components using primary organoid co-cultures representative of the tumor microenvironment. These models promise to facilitate the study of tumor-stroma and tumor-immune interaction and may be valuable for the assessment of immunotherapeutics such as checkpoint inhibitors.
Development of primary human pancreatic cancer organoids, matched stromal and immune cells and 3D tumor microenvironment models
Michael A. James
Added on: 07-01-2021
Comparison between 2D and 3D models of breast cancer
2018
New Mexico State University, Las Cruces, USA
The study describes the development of a hydrogel-based 3D model of breast cancer. A comparison between this 3D model and traditional 2D monolayer cultures show that the morphometric characteristics of human breast cancer cells in 3D conditions recapitulate more accurately these in "in vivo" conditions. Several imaging techniques confirm the potential of using this model for drug testing.
Morphometric analysis of a triple negative breast cancer cell line in hydrogel and monolayer culture environments
Elba E Serrano
Added on: 07-14-2021
Dosing of cancer immunotherapy predicted using mathematical modelling
Company 2018
Roche Innovation Center, Basel, Switzerland
The success of immunocytokine-based cancer immunotherapy depends on achieving optimal concentrations of the drugs within the tumor microenvironment. The intratumoral immunocytokine concentration is a complex product of administered drug dose, treatment schedule, and anatomic/ spatial factors. In this study, the researchers utilized sequential pharmacokinetic and imaging data from patients treated with a novel tumor-targeted immunocytokine to generate a mathematical model. The model was able to predict antibody tumor uptake in patients after repeated administrations and identify an optimal dosing regimen.
Prediction of the optimal dosing regimen using a mathematical model of tumor uptake for immunocytokine-based cancer immunotherapy
Benjamin Ribba
Added on: 07-26-2021
Generation and in vitro testing of cancer immunotherapy from new subset of immune cells
2018
University College London Institute of Child Health, London, United Kingdom
Adoptive cellular therapy with T cells engineered to express chimeric antigen receptors (CARs) combines the antigen specificity of a monoclonal antibody with potent T cell activation, proliferative potential, and cytotoxic function. In the present study, the researchers sought to modify gamma delta T (gdT) lymphocytes to incorporate CARs to enhance their cytotoxicity while retaining their ability to migrate to tumors. The researchers transduced cells isolated from donors peripheral blood and tested them for cytotoxicity, migration capacity and antigen presentation using in vitro assays. The study shows that gamma delta T (gdT) including CAR have the capacity for migration and for uptake and cross-presentation of tumor-associated antigens, which was a potential advantage over conventional CAR-T cells, especially in the treatment of solid tumor.
Chimeric antigen receptor-engineered human gamma delta T cells: enhanced cytotoxicity with retention of cross presentation
John Anderson, Barry Flutter
Added on: 07-28-2021
In silico analysis of colorectal cancer patients genetic variations
2018
German Cancer Research Center (DKFZ), Heidelberg, Germany
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer mortality worldwide. Aberrant expression of genes NLRC5 and PD-L1 have been reported in CRC. In the present study, the researchers aimed at selecting potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools and investigating their influence on CRC risk in a cohort of 1424 patients. The data suggests that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of CRC, providing therefore novel biological information, which could eventually improve CRC risk management but also immunotherapy in CRC.
Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer
Calogerina Catalano
Added on: 09-18-2021
Matrix stiffness can regulate cancer cell invasion
2018
The University of Alabama, Tuscaloosa, USA
Breast cancer brain metastasis is a fatal process in the late stages of breast cancer that rapidly leads to death. One of the critical factors mediating brain invasion is the physicochemical cues of the brain microenvironment and how they modulate tumor cells. However, the mechanisms underlying these interactions remain unclear due to the difficulties of accurately replicating the brain microenvironment in vitro. Here, a hyaluronic acid hydrogel platform is used to assess the influence of matrix stiffness on a brain metastasizing variant of a triple-negative breast cancer cell line. The results showed that there was a positive correlation between cell invasion and hydrogel stiffness. Additionally, the signalling pathway activated by the response to matrix stiffness was identified. Overall, the researchers develop a tunable system that allows elucidating the mechanisms that modulate cancer cell metastatic behaviour that depends on matrix stiffness and demonstrates that the mechanical properties of the tumor microenvironments can influence cancer progression.
The influence of matrix stiffness on the behavior of brain metastatic breast cancer cells in a biomimetic hyaluronic acid hydrogel platform
Shreyas S Rao
Akshay A Narkhede et al. Journal of Biomedical Materials Research Part A 2018 [491]
EURL ECVAM [492]
Added on: 11-01-2021
Novel 3D model of glioblastoma with controllable tumor microenvironment
2018
City University of Hong Kong, Hong Kong, Hong Kong SAR of China(1)
New York University, Brooklyn, USA(2)
New York University, Brooklyn, USA(2)
A novel glioblastoma 3D model is generated and preclinically tested incororating microfluidic angiogenesis, controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, inflammatory milieu and extracellular matrix mechanics is critical for preclinical anti-angiogenic therapeutic screening and has not been integrated in vitro model until now.
Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis
Raymond H. W. Lam(1), Weiqiang Chen(2)
Added on: 07-01-2021
Small intestine-on-a-chip using biopsy-derived organoids show physiological functions and near in-vivo- gene expression
2018
Harvard University, Boston, USA
The intestinal chip contains human intestinal epithelial cells derived from organoids or biopsies as well as tissue-specific microvascular endothelial cells of the intestine. Among other things, it exhibits 3D intestinal villi-like structures, multi-line differentiation, epithelial barrier function, enzymatic activity of the brush border enzyme and mucus production. Together with intestinal stem cells there are nutrient-digesting and absorbing enterocytes, mucus-producing goblet cells, hormone-secreting enteroendocrine cells, and microbiome-regulating and sensory Paneth cells. Peristalsis and nutrient flow are also simulated. The transcriptome of the intestinal chip is similar to that of the adult human duodenum in vivo. Since the microenvironment can be maintained for weeks, they allow both short and longer-term studies; in the long term, this will allow a better understanding of human-microbiome interactions, the modelling of malnutritional and inflammatory bowel disorders, and the performance of personalised drug testing.
Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids
Donald E. Ingber
Added on: 05-26-2020
Tumor model platform with microvasculature for drug testing
2018
Auburn University, Auburn, USA
In this work, a model consisting of a bioengineered, chip-based 3D cancer model with microvasculature is developed. This new multicellular model allows the interactions of different cell types and microenvironments to be studied through the vasculature and provides a new platform for drug testing in preclinical studies.
A microvascularized tumor-mimetic platform for assessing anti-cancer drug efficacy
Elizabeth A. Lipke
Added on: 07-02-2021
Characterization of immune response in renal carcinoma tumors from patients
2018
Copenhagen University Hospital, Herlev, Denmark
Adoptive cell therapy (ACT), based on the infusion of expanded autologous tumor-infiltrating lymphocytes (TIL), has demonstrated durable complete tumor regressions in metastatic melanoma. However, results for renal cell carcinoma (RCC) have been dismal as far as now. In the present study, the researchers have characterized the presence and activity of T cells using autologous tumor cell lines from RCC patients and compared them to ones generated from metastatic melanoma patients. TILs from primary RCC specimens could be isolated from the patients, expanded ex vivo, and could recognize tumors cell lines in vitro. T-cell responses were detected in the majority of RCCs analyzed. Extensive in vitro characterization of TILs revealed a unique functional pattern, with weaker responses compared with metastatic melanoma. These findings have relevance for the development of ACT for patients with RCC.
T-cell responses in the microenvironment of primary renal cell carcinoma—implications for adoptive cell therapy
Marco Donia, Inge Marie Svane
Added on: 09-14-2021
Drug sensitivity depends on cancer cell-extracellular matrix interactions
2018
Griffith University, Brisbane, Australia
One of the main limitations in cancer therapy is drug resistance from cancer cells. This can be due to de novo mechanisms acquired by the cells during normal cancer progression. However, traditional 2D models have limitations in faithfully replicating cell behaviour in vitro. Here, a 3D model based on Matrigel-embedded human breast cancer cells is used to investigate the response of cancer cells to doxorubicin and the potential acquisition of drug resistance. The results showed that the response of cancer cells grown in 3D conditions to doxorubicin are different compared to those in traditional models. Despite the reduced proliferation of cancer cells in 3D conditions, an increase in pro-survival proteins was observed following exposure to doxorubicin. Furthermore, interactions between the extracellular matrix and cancer cells were identified to be critical for the development of drug resistance. Accordingly, combining the inhibition of integrins signalling with doxorubicin could counteract the effect of this interplay and reduce breast cancer cell viability. Overall, the researchers present a new model that allows to study complex interactions of cancer cells with their environment and elucidate potential mechanisms that contribute to drug sensitivity.
Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins
Vicky M Avery
Added on: 10-20-2021
Lung-on-a-chip to perform drug screening
2018
Shanghai University, Shanghai, China
Organ-on-a-chip models are gaining interest to perform drug testing, due to their capacities in replicating in vitro pathophysiological features of different organs. Here, a custom organ-on-a-chip scaffold was built with biofabrication techniques and cultured with human non-small cell lung cancer cells and human fetal lung fibroblasts to model the alveolar microenvironment and evaluate gefitinib as an anti-tumor drug. The results showed that there is a potential interplay between both cell types driving cell resistance of cancer cells. Moreover, when they were co-cultured with human umbilical endothelial cells, cancer cells led to a decrease in endothelial cell viability and triggered metastatic behaviour. Overall, the researchers propose an easy-to-adjust lung-on-a-chip model with the potential to be used in personalized medicine and high-throughput drug screening.
Nanofiber membrane supported lung-on-a-chip microdevice for anti-cancer drug testing
Xinghua Gao
Added on: 11-28-2021
Microfluidic tumor-on-chip for breast cancer bone metastasis
2018
Columbia University, New York, USA(1)
Politecnico di Milano, Milan, Italy(2)
Politecnico di Milano, Milan, Italy(2)
Bone metastasis is a very common feature of breast cancer progression. It has been shown that tumor cells circulate in the vasculature and can colonize perivascular areas where they form niches that are regulated by neighbour cells. However, the mechanisms driving these interactions are poorly understood. Here, a combination of human endothelial cells, mesenchymal stem cells and breast cancer cells is cultured on a 3D native bone matrix in a microfluidic chip with stable vascular networks to investigate the interplay between these cell types in a 3D microenvironment. The results show that the control of the physicochemical cues of the niche-on-a-chip could regulate the assembling of the vascular network. Moreover, perivascular mesenchymal stem cells supported processes related to angiogenesis. In these niches, breast cancer cells persisted in a slow-proliferative state related to increased resistance to sunitinib treatment. In this study, the researchers develop a model which allows the modulation of physiochemical cues to regulate cancer cell behaviour and could potentially help to elucidate metastasis mechanisms of colonization and drug resistance.
Human bone perivascular niche-on-a-chip for studying metastatic colonization
Gordana Vunjak-Novakovic(1), Manuela Teresa Raimondi(2)
Added on: 10-08-2021
New microRNA linked to coronary artery disease characterized in cultured human cells
2018
Fujian Medical University Union Hospital, Fuzhou, China
Coronary artery disease (CAD) is the main cause of death and disability worldwide. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression at the post-transcriptional level, some circulating miRNAs have been reported that could monitor several cardiovascular disease processes. One miRNA of interest is miR-574-5p which expression is notably increased in the sera of patients with CAD. In the present study, the researchers aimed at gaining knowledge on the specific mechanisms by which miR-574-5p affects CAD. The researchers isolated sera from CAD patients and detected an increased expression level of miR-574-5p. Vascular smooth muscle cells (VSMCs) are known to have aberrant proliferation in CAD. Also, miR-574-5p was introduced into VSMCs cultured in vitro which resulted in increased cell proliferation and inhibited apoptosis. Further, the researchers showed that miR-574-5p in those cells specifically regulated a gene called ZDHHC14 which has been traditionally linked to cancer. Overall the study reveals miR-574-5p as a potential target for CAD treatment.
MicroRNA-574-5p promotes cell growth of vascular smooth muscle cells in the progression of coronary artery disease
Liangcheng Zhang
Added on: 11-29-2021
miR-155 can regulate cancer-related features in breast cancer cells
2018
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Breast cancer remains one of the most prevalent and deadly cancers affecting women. In recent years, microRNAs have been identified as critical regulators in several types of cancers. Here, a human breast cancer cell line in different culture setups was used to investigate the miR-155-dependent modulation of proliferation and migration in breast cancer cells. The results showed that miR-155 mimics enhanced the expression of miR-155, whereas miR-155 inhibitors had the opposite effect. Furthermore, breast cancer cells transfected with miR-155 mimics had increased proliferation and migration, contrary to the decreased proliferation seen in the same cells treated with a miR-155 inhibitor. Finally, SOCS1 and MMP16 were identified as target proteins regulated by miR-155. Overall, the researchers confirm that miR-155 can influence breast cancer cell proliferation and migration via the modulation of target genes, which could make it a potential novel target for cancer therapy.
MiR-155 promotes the proliferation and migration of breast cancer cells via targeting SOCS1 and MMP16
Gui-Long Guo
Added on: 11-01-2021
A new 3D system to study multicellular tumor dynamics
December 2017
University of Freiburg, Freiburg, Germany
The study describes the development of a new method through the biofabrication of conical hydrogel wells to develop 3D spheroids of all types of cells, even of low-adhesive cells that usually do not form stable aggregates. Furthermore, the method allows the combination of different cell types to form multicellular aggregates and it provides direct access to the cell aggregates to use for different assays. With this method, the researchers show that bone marrow stromal cells enhance breast cancer cells 3D growth.
A deep conical agarose microwell array for adhesion independent three-dimensional cell culture and dynamic volume measurement
Per G. Lund
Added on: 07-11-2021
A system for multicellular aggregates
December 2017
Department of Radiation Oncology, Medical Center – University of Freiburg, Freiburg, Germany
Spheroid use in oncological studies is limited by the capabilities of different cell types to self-assemble into 3D spheroids. This study describes a high-precision micro-molding technique that produces deep conical agarose microwell arrays that allow the cultivation of uniform multicellular aggregates, irrespective of the spheroid formation capacity of the cells. Such hydrogel arrays warrant a steady nutrient supply for several weeks, permit live volumetric measurements to monitor cell growth, enable immunohistochemical staining, fluorescence-based microscopy, and facilitate immediate harvesting of cell aggregates. The co-culture of a breast cancer cell line with bone marrow stromal cells is shown to enhance the 3D growth of the cancer cells in this system.
A deep conical agarose microwell array for adhesion independent three-dimensional cell culture and dynamic volume measurement
Per G. Lund, Andreas R. Thomsen
Added on: 04-21-2020
Immune response analysis from ex vivo tissues from patients treated with immune checkpoint molecules
December 2017
National Cancer Center, Tokyo, Japan
Immune checkpoint molecules have durable clinical benefits in various types of cancers. Yet the clinical response is heterogeneous and highlights the need to identify biomarkers to better predict the response. In this study, the researchers explored comprehensive immune cell responses associated with clinical benefits using peripheral blood from patients with malignant melanoma treated with anti-PD-1 monoclonal antibodies. Pre- and post-treatment samples were collected and subjected to mass cytometry assays that measured the expression levels of proteins linked to immune responses. The study shows an increase of a subset of immune cells which can be used as a predictor of clinical response to PD-1 blockade therapy in patients with malignant melanoma.
Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma
Hiroyoshi Nishikawa
Added on: 07-29-2021
Immune response analysis in gastric cancer patient's tissues
December 2017
The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Gastric cancer (GC) is one of the leading causes of mortality worldwide. Investigations showed that T-cell dysfunction is crucial to understand human tumor growth. Currently, there is little detail of T-cell subsets resident within gastric cancer tissues or the expression patterns in this microenvironment. In the present study, the researchers investigated the distribution of T-cells subset, the differentiation and inhibitory phenotype of T-cells from blood and tissues of GC patients. Phenotypic analysis was based on the isolation of tumor-infiltrating lymphocytes. The study characterizes a specific T-cell subsets resident within GC whose behaviour could be corrected to tumor infiltration using blockade inhibitor. The study underlines the need for a holistic view of immune response in cancer to design proper therapy.
Tumor-infiltrating CD4+ T cells in patients with gastric cancer
Quanli Gao
Added on: 09-15-2021
In vitro testing of engineered T cells to increase tumor homing
December 2017
Herlev University Hospital, Herlev, Denmark
One of the major obstacles for successful adoptive cell therapy (ACT), is the limited homing of effector T cells to immune-suppressive tumor sites. In the present study, the researchers aimed at equipping T cells with chemokine receptors matching the chemokines of the tumor microenvironment to improve homing. Using flow cytometry, T cells were analysed from malignant ascites and blood donors (ovarian cancer patients and healthy individuals). The researchers characterized the chemokine profile in ascites chemokines and the expression of corresponding receptors on circulating T cells and tumor ascites lymphocytes. Chemokine receptor was then transduced and showed increased migration towards tumors in vitro. This proof of concept study shows that chemokine receptor engineering is feasible and improves homing of transduced T cells towards the tumor microenvironment.
Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
Manja Idorn
Added on: 07-29-2021
Influence of culture substrates in cancer cell biology
December 2017
Trinity College Dublin, Dublin, Ireland
3D in vitro models are increasingly used to reproduce key features of cancer biology in drug discovery. However, culture substrates remain poorly characterized, and it is still unknown how they influence cancer cell responses to drug testing. Here, 2D and 3D cultures of human adenocarcinoma cells are used to evaluate the influence of different substrates in the morphological, mechanical and biochemical properties of the cells. The results offer a proper evaluation of cell features when growing on soft 3D substrates or two-dimensional glass surfaces. Moreover, drug response to docetaxel was evaluated in different culture conditions. Overall, this study provides a deep characterization of a human adenocarcinoma cell line and the potential of its use in 3D systems for lung cancer research.
Culturing substrates influence the morphological, mechanical and biochemical features of lung adenocarcinoma cells cultured in 2D or 3D
Dania Movia
Added on: 11-22-2021
Photodynamic therapy tested in vitro on cancer cell lines
December 2017
Oslo University Hospital, Oslo, Norway(1)
University of Oslo, Oslo, Norway(2)
University of Oslo, Oslo, Norway(2)
5-Fluorouracil (5-FU) is one of the standard chemotherapy drugs used to treat pancreatic cancer. However, treatment only extends survival modestly, and disease recurrence is typical due to drug resistance. CD105 (Endoglin) is a cell-surface glycoprotein whose level is elevated in tissues undergoing active angiogenesis, such as regenerating and inflamed tissues or tumours. The expression of CD105 on tumour-associated blood vessels makes CD105 an interesting target for therapy. Photochemical internalization (PCI) is a drug delivery technology for local and light controlled cytosolic release of therapeutics confined in the illuminated area only. In the present study, the researchers used in vitro experiments conducted on pancreatic cancer lines to show the feasibility of photodynamic therapy by sensitizing the cells to FU treatment and a controlled release of a CD105 antibody. This novel approach could be used as a dual anti-angiogenesis and anti-tumor cell strategy for cancer therapy.
5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105-saporin
Pål Kristian Selbo(1), Kaja Lund(2)
Added on: 09-15-2021
Quantitative method to characterize cell morphology
December 2017
The Catholic University of America, Washington, USA
In this study, human breast cancer cells were cultured in different substrates to classify them depending on their morphology. Digital holographic microscopy coupled with epifluorescence microscopy were used to relate cell phase parameters to actin features. A machine learning method was used to classify the morphologies of cancer cells. The results showed that this method has high accuracy in classifying cell morphologies, which makes it a useful method to monitor cancer cell morphology features.
Quantitative assessment of cancer cell morphology and motility using telecentric digital holographic microscopy and machine learning
Christopher B Raub
Added on: 08-01-2021
3D lung cancer invasion model
November 2017
University of Geneva, Geneva, Switzerland
Lung diseases commonly drive to fatal events, like cancer, which reaches a mortality rate of 70% within 1 year after diagnosis. However, there is a lack of effective tools to efficiently diagnose lung cancer at early stages. Autofluorescence bronchoscopy is a promising tool to distinguish between cancerous and healthy lung tissues, but needs further optimization to be efficient. Here, a 3D model is developed, reproducing the human lung cancer cells invasion of a functional airway. The model contains human airway epithelial cells, human lung fibroblasts and human lung adenocarcinoma cells, allowing to test the potential of two-photon laser induced autofluorescence in order to discriminate healthy and carcinogenic tissues. The results showed that autofluorescence can be detected similarly like in patient's tissue samples and can be related to the health status. Moreover, the edges of the tumors had spectral and intensity heterogeneity, showing that metabolic changes in the tumor influence its microenvironment. Overall, the researchers provide a new model that can be used to extend the research on lung cancer and improve the efficiency of autofluorescence-based diagnostic tools.
Health state dependent multiphoton induced autofluorescence in human 3D in vitro lung cancer model
Vasyl Kilin
Added on: 11-22-2021
Breast cancer profiling with transcriptomic analysis
November 2017
University of Granada, Granada, Spain
A combination of heterogeneous transcriptomics datasets is used to generate a new model to profile human breast cancer to increase the robustness of the results. This method allowed for the identification of 98 potential biomarkers that, after a classification and selection process, were reduced to 6 gene markers for breast cancer diagnosis. In summary, this study presents a new tool to classify and diagnose human breast cancer.
Integration of RNA-Seq data with heterogeneous microarray data for breast cancer profiling
Daniel Castillo
Added on: 07-30-2021
Ex vivo stimulation of immune response against cancer with a new antigen
November 2017
Copenhagen University Hospital, Herlev, Denmark
The PD-1/PD-L1 pathway in cancer has been extensively studied whereas PD-L2 has received less attention. In the present study, the researchers used ex vivo methods to study spontaneous specific T-cell reactivity against two epitopes of PD-L2 from samples of cancer patients and healthy donors. An immune response to PD-L2 was observed, which interestingly did not cross-react with PD-L1 response. These results suggest that activating PD-L2 specific T cells might be an attractive strategy for anti-cancer immunotherapy.
The inhibitory checkpoint, PD-L2, is a target for effector T cells: Novel possibilities for immune therapy
Mads Hald Andersen
Added on: 07-29-2021
In vitro tool to characterize adoptive immunotherapy against cancer
CompanyNovember 2017
IsoPlexis Corporation, Branford, USA(1)
Novartis Pharmaceuticals, Cambridge, USA(2)
Novartis Pharmaceuticals, Cambridge, USA(2)
Adoptive immunotherapy is a novel treatment modality for human cancers and involves the use of viral vectors to genetically modify autologous T cells to express a chimeric antigen receptor (CAR) directed against a tumor antigen. As of today, the characterization of the functional attributes of CAR-T cell products is still a challenge. In the present study, the researchers generated an in vitro method for single-cell profiling of CAR-T pre-infusion products prepared from healthy donors together with a bioinformatics tool to visualize the results. The system provides a more sensitive and comprehensive functional assessment CAR-T pre-infusion products and may provide insights into the safety and efficacy of CAR-T cell therapy.
Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigenspecific response
Jing Zhou(1), Qiong Xue(2)
Added on: 07-26-2021
Melanoma cell lines show high-level expression of markers targeted by immunotherapy
November 2017
Lewis Katz School of Medicine at Temple University, Philadelphia, USA
Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is a glycoprotein expressed on the surface of activated T cells; it acts as a potent inhibitor of the cytotoxic T lymphocyte activation and thus a key negative regulator of anti-tumor activity. Thus, Anti-CTLA4 immunotherapy is highly effective at reactivating T cell responses against cancer, in particular melanoma. In the present study, the researchers show that CTLA-4 is also highly expressed by most human melanoma cell lines. Also, the researchers checked by RNA sequencing the upregulation of genes downstream of molecular cascades triggered by CTLA-4. Taken together, the results raise the possibility that CTLA-4 targeting on melanoma cells may contribute to the clinical immunobiology of anti-CTLA-4 responses.
Interferon-gamma signaling in melanocytes and melanoma cells regulates expression of CTLA-4
M. Raza Zaidi
Added on: 09-13-2021
A non-invasive method to assess patients' response to immunotherapy
October 2017
UC San Diego Moores Cancer Center, La Jolla, USA
Checkpoint inhibitor-based immunotherapy has revolutionized treatment for cancer malignancies. Alas, immune-related adverse effects are not negligible and some patients do not respond to therapy. For these reasons, it has become evident that predictive biomarkers of response are needed for these novel agents. Recently, tumor mutational burden, as detected by tissue next-generation sequencing, has been shown to correlate with response to checkpoint inhibitors in several malignancies. In the present study, the researchers sought to investigate the association between hypermutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response to avoid tissue biopsy which is costly and invasive. The researchers assessed the association by next-generation sequencing in 69 patients with diverse malignancies over time. The study demonstrates a correlation between high alteration number detected in blood-derived circulating tumor DNA and favourable outcomes, including overall response, progression-free and overall survival with checkpoint inhibitor-based immunotherapy. This data shows liquid biopsy to be a viable, non-invasive, predictive biomarker for checkpoint inhibitor response.
Hypermutated circulating tumor DNA: correlation with response to checkpoint inhibitor-based immunotherapy
Yulian Khagi
Added on: 09-14-2021
Chips to study the effects of extracellular matrix architecture
October 2017
Eindhoven University of Technology, Eindhoven, Netherlands
One of the most important elements of the tumour microenvironment is the extracellular matrix. However, how it influences cell invasion remains elusive due to difficulties in identifying individual contributors in current models. Thus, it is necessary to find new strategies that allow the investigation of the interplay between tumours and the extracellular matrix. In this study, a new microfabrication method is used to integrate layers that mimic extracellular matrix between two microfluidic channels to resolve the influence of matrix architecture on human breast cancer cell invasion. It was possible to integrate two biofabricated matrices with different fibre sizes in one chip. The results showed that the diameter of fibres composing the extracellular matrix had no effects on cell morphology or invasion distance, but smaller fibre sizes did induce more and longer protrusions. The researchers propose a new microfluidic system that allows elucidating the role of individual elements of the tumour microenvironment and that could potentially be used to investigate other biological processes in cell culture setups.
A novel method to understand tumor cell invasion: integrating extracellular matrix mimicking layers in microfluidic chips by “selective curing”
J M J den Toonder
Added on: 10-11-2021
In vitro analysis of combination of cytokines and inhibitors of immunosuppression on cancer cells
October 2017
IRCCS for Oncology, Genoa, Italy
Small Cell Lung Cancer (SCLC) is an aggressive tumor characterized by rapid and extensive metastatic dissemination, recurrence after chemotherapy and poor prognosis. Recently, immunotherapy with anti-PD-1 antibodies has shown clinical benefit in recurrent Small Cell Lung Cancer (SCLC). In the present study, the researchers aimed at better understanding the mechanism that promotes reactivation of anti-tumor Cytotoxic T Lymphocyte (CTL) responses. Human SCLC cell lines were treated in vitro with different cytokines together with anti-PD-1 and analysed by flow cytometry and quantitative measurements of RNA. One cytokine was characterized as having a specific capacity to enhance the effects of anti-PD-1 which should be exploited as a potential combinatorial therapeutic strategy.
IL-27 mediates HLA class I up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient small cell lung cancer cells
Marina Fabbi, Silvano Ferrini
Grazia Carbotti et al. Journal of Experimental & Clinical Cancer Research 2017 [541]
EURL ECVAM [542]
Added on: 09-15-2021
Modulation of hydrogels physiochemical cues to optimize tumor modelling
October 2017
University of Toronto, Toronto, Canada
The use of modulable hyaluronan hydrogels is analysed to better mimic the physiochemical properties of tumor microenvironments. After screening, the optimal hydrogel gives the best environment for human 3D breast cancer spheroids to reproduce their drug resistance mechanisms. Thus, these hydrogels can perform better than common Matrigel-based methods in drug screening assays.
Independently tuning the biochemical and mechanical properties of 3D hyaluronan-based hydrogels with oxime and Diels–Alder chemistry to culture breast cancer spheroids
Molly S Shoichet
Added on: 07-14-2021
Next Generation Sequencing allows identification of new mutations related to lung cancer
October 2017
Icahn School of Medicine at Mount Sinai, New York, USA
Lung cancer remains the most prevalent cancer and the leading cause of cancer mortality. Genetic and genomic profiling in lung cancers has not only facilitated the understanding of the molecular mechanisms of pathogenesis but also significantly impacted clinical practice. In the USA, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend genetic testing for seven genes (EGFR, ALK, ROS1, RET, BRAF, MET, HER2) with available targeted therapies. In the present study, the researchers analyzed by Next Generation Sequencing a total of 932 lung cancer patients samples to detect various mutations in 50 cancer-related genes. The goal of the study was to expand the landscape of genetic mutations (i.e. not yet included in the NCCN guideline) that could inform clinical decisions. Results allowed identification of activating mutations in additional genes JAK2 and JAK3 with clinical implications. The study concludes that Next Generation Sequencing should allow better clinical decisions.
Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications
Fei Ye, Rong Chen
Added on: 09-17-2021
Nitric oxide hinders estrogen-induced apoptosis in breast cancer
October 2017
Bar Ilan University, Ramat Gan, Israel
Estrogen-induced apoptosis is an effective treatment in postmenopausal metastatic estrogen receptor-positive breast cancer patients. However, the role of nitric oxide in the response to estrogen treatment has been generally overlooked. Here, estrogen-induced apoptosis is induced in a 3D culture of a human breast cancer cell line to investigate the impact of nitric oxide before and after the estrogen treatment. The results showed that treated spheroids exhibited downregulation of pathological features. However, treatment with low concentrations of nitric oxide increased cell survival and counteracted the effects of estrogen-induced apoptosis. On the contrary, high concentrations of nitric oxide promoted slower metabolism and cell death. Overall, the researchers demonstrate that low concentrations of nitric oxide can hinder the effectiveness of estrogen-induced apoptosis, which may lead to further exploration of strategies to block nitric oxide activity in breast cancer patients.
Nitric oxide is cytoprotective to breast cancer spheroids vulnerable to estrogen-induced apoptosis
Mordechai Deutsch
Added on: 10-30-2021
3D matrix to model breast cancer bone metastasis
2017
Politecnico di Milano, Milan, Italy
Breast cancer is a highly prevalent disease with a bad prognosis in women. In many cases, breast cancer bone metastasis is a common step of cancer progression. However, the mechanisms that induce this invasive behaviour on this specific microenvironment are poorly understood. Current models have severe limitations in reproducing the key features of breast cancer cells interplay with bone tissue. In recent years, 3D models are becoming a popular choice due to their associated advantages in better replicating in vivo cell behaviour. Here, a poly-ether-urethane foam is used to build a 3D structure to study the interactions between human breast cancer cells and the bone microenvironment. The results showed that the foam matrix correctly supported the culture of human osteoblasts and their differentiation from human adipose-derived stem cells. Moreover, it was possible to co-culture them with breast cancer-derived tumor-initiating cells, which induced the generation of tumor aggregates. Overall, the researchers propose a new material to build matrices that support the generation of a 3D bone microenvironment in vitro to study the breast cancer cell invasion of bone tissue in a human context.
Polyurethane foam scaffold as in vitro model for breast cancer bone metastasis
Silvia Farè
Added on: 10-08-2021
CAR T-cells to target ERBB2 tumors
2017
Universiti Putra Malaysia, Serdang, Malaysia
The study describes the production of chimeric antigen receptor T-cells that target human epidermal growth factor receptor 2 overexpressing human breast tumors. When co-culturing these modified T-cells with a human breast cancer cell line, there was a significant increase in apoptosis compared to non-modified T-cells. This strategy can be a potential tool to use immunotherapy against human epidermal growth factor receptor 2 expressing tumors.
Human CD3+ T-cells with the anti-ERBB2 chimeric antigen receptor exhibit efficient targeting and induce apoptosis in ERBB2 overexpressing breast cancer cells
Pooi Ling Mok
Rusheni Munisvaradass et al. International Journal of Molecular Sciences 2017 [551]
EURL ECVAM [552]
Added on: 07-31-2021
Drug test in 3D model shows new insights in cancer stem cell response
2017
Boston University, Boston, USA
Two chemotherapeutic agents (Paclitaxel and Cisplatin) show differential responses in three different human breast cancer models. The different dynamics in the three different models give key insights into the mechanisms of these drugs and the cancer stem cell responses. Overall, the 3D multicellular model is has a great potential to recreate the different interactions and dynamics in human breast tumor microenvironments in vitro .
Breast cancer spheroids reveal a differential cancer stem cell response to chemotherapeutic treatment
Mark W Grinstaff, Muhammad H Zaman
Added on: 07-14-2021
Ex vivo and in vitro screening and expansion of immune cells of a patient with capacities for immunotherapy
2017
University of British Columbia, Vancouver, Canada
The success of several forms of immunotherapy depends entirely on the presence of mutated cancer antigens, or neoantigens. Adoptive cell therapy (ACT) against neoantigens will require reliable methods to isolate and expand rare, neoantigen-specific T cells from clinically available biospecimens. In the present study, the researchers used in vitro screening of small quantities of peripheral blood from multiple time points from an ovarian cancer patient to recognize peptides corresponding to
the patient's tumor somatic mutation. The researchers identified different T cell lines, which collectively recognized mutations peptides. Some lines could be expanded ex vivo from peripheral blood prior to the first tumor recurrence. Thus, neoantigen-specific T cells can be expanded from small volumes of blood during tumor remission, making pre-emptive ACT a plausible clinical strategy.
A library-based screening method identifies neoantigen-reactive T cells in peripheral blood prior to relapse of ovarian cancer
Brad H. Nelson
Added on: 07-29-2021
Mathematical modelling to improve immunotherapy design for colorectal cancer
2017
University Hospital Heidelberg, Heidelberg, Germany
To improve immunotherapy results in colorectal cancer patients, a better understanding of the complex immunological interplay within the microenvironment is crucial. In this study, the researchers generated a mathematical model from quantitative histological data from cancer patients. This model incorporates stochastic interactions between tumor cells, immune cells, and stroma and faithfully represents diverse spatial patterns observed in histological samples of human colorectal cancer tissue. This model was then used to systematically test the effect of different therapeutic interventions on this system and to create specific recommendations for effective
immunotherapies.
In silico modeling of immunotherapy and stroma- targeting therapies in human colorectal cancer
Niels Halama
Added on: 07-26-2021
Software for tumor clonal classification
2017
Washington University School of Medicine, Saint Louis, USA
Software is developed to overcome the error rates in clonal ordering in the study of tumour progression. Using a bootstrap resampling technique, that takes into account statistical variability, it is possible to identify the sample origin and subclones. This method outperformed three other widely used tools and was able to identify and classify subclones in different clinical samples of leukaemia and breast cancer; showing the potential to monitor clonal populations in tumour biopsies or to guide personalised medicine.
ClonEvol: clonal ordering and visualization in cancer sequencing
Christopher A Maher
Added on: 07-28-2021
Subset of immune cells shown to influence outcome of bladder cancer patients
2017
University of Birmingham, Birmingham, United Kingdom
Bladder cancer is the seventh most common cancer in Western society. To be able to design immunotherapy, the tumour immune microenvironment has to be better understood. In the present study, the researchers studied the tumors of 114 patients by immunocytochemistry used a panel of markers for innate and adaptive immune cells. A specific profile of immune cells was characterized. This subtype of immune cells was isolated from donors and co-cultured in vitro with cancer cells and confirmed to induce changes in function and gene expression profile. Finally, the researchers assessed the presence of these immune cells in patients and showed that an increased number of those cells was associated with improved survival, indicative of a novel mechanism for immunotherapy.
Interleukin-17-positive mast cells influence outcomes from BCG for patients with CIS: Data from a comprehensive characterisation of the immune microenvironment of urothelial bladder cancer
Richard T. Bryan
Added on: 09-18-2021
Cancer promoting activity of cancer marker shown in vitro
2017
Soochow University, Jiangsu Changzhou, China(1)
University of Pittsburgh, Pittsburgh, USA(2)
University of Pittsburgh, Pittsburgh, USA(2)
PD-L1 is an immunomodulatory ligand that negatively regulates T cell activation, numerous studies have shown that many human cancers display PD-L1 over-expression which correlates with patients’ prognosis. Clinical studies have demonstrated that PD-L1 blockade can significantly inhibit tumor progression and improve patient prognosis. In the present study, the researchers aimed at understanding better the biological functions of PD-L1 in cancer cells. PD-L1 was shut on and off in oesophagal cancer cell lines to study its function and showed that PD-L1 expression significantly promoted the cell viability, migration and phenotypes associated with epithelial-to-mesenchymal transition (a hallmark of cancer). The present study reveals a tumor cell-autonomous role of PD-L1 signalling which strengthens its potential as treatment target.
PD-L1 expression promotes epithelial to mesenchymal transition in human esophageal cancer
Jingting Jiang(1), Binfeng Lu(2)
Added on: 09-14-2021
Cancer-associated fibroblasts modulate breast cancer cells
2017
Zhujiang Hospital of Southern Medical University, Guangzhou, China
Cancer-associated fibroblasts have been described to be related to cancer development and progression. However, little is known about the effect of cancer-associated fibroblasts autophagy on triple-negative breast cancer cells. Here, human fibroblasts from patients with invasive triple-negative breast cancer were co-cultured with human triple-negative breast cancer cells to evaluate the effect of fibroblast autophagy on cancer cell growth. The results showed that cancer-associated fibroblasts had significantly higher levels of autophagy-related proteins. Moreover, cancer-associated fibroblasts conditioned media induced metastatic behaviour and changes in the levels of vimentin, N- and E-cadherin in triple-negative breast cancer cells. Finally, key proteins in the Wnt/beta-catenin pathway were upregulated in conditioned media treated cells. Overall, the researchers demonstrate that cancer-associated fibroblasts autophagy increases metastatic features in triple-negative breast cancer cells and upregulates epithelial-to-mesenchymal transition through Wnt/beta-catenin, opening new possibilities in the development of cancer targets.
Cancer-associated fibroblasts autophagy enhances progression of triple-negative breast cancer cells
Aiguo Wu
Added on: 10-27-2021
Microfluidic platform to investigate mechanisms of drug transport
2017
Temple University, Philadelphia, USA
Tumor drug delivery is a complex process where several elements of the environment are involved. However, there are some difficulties associated with the study of drug delivery in vivo. Thus, there is a need to better replicate tumor microenvironment in simplified models. Here, a microfluidic device is developed to replicate the tumor microenvironment with the co-culture of human breast cancer cells and endothelial cells in a 3D context to elucidate the key mechanisms that determine drug delivery efficiency. The results showed that endothelial cell permeability increased when exposed to tumor cells or tumor cell-conditioned media. Furthermore, metastatic cells induced even higher permeability than non-metastatic ones, possibly through the impairment of endothelial cell-cell junctions. Overall, the researchers propose a new platform to study the different features of tumor microenvironment that affect drug delivery, which could be potentially used for drug screening or to elucidate transendothelial drug transport mechanisms.
A biomimetic microfluidic tumor microenvironment platform mimicking the EPR effect for rapid screening of drug delivery systems
Mohammad F Kiani
Added on: 10-21-2021
New compound tested as treatment for rheumatoid arthritis using human cell lines and patients cells
2017
Duke University, Durham, USA(1)
University of Texas, Dallas, USA(2)
University of Texas, Dallas, USA(2)
TNF-α is a major contributor to tissue inflammation and inhibition of its signalling cascade has been proven to reduce disease burden for rheumatoid arthritis (RA), ankylosing spondylitis, and inflammatory bowel disease. TAK1 acts as a key mediator in TNF-α-mediated signalling. In the present study, the researchers aimed at describing the newly synthesized compound Takinib, a potent and selective TAK1 inhibitor. The compound was studied using a variety of human cell lines and cells isolated from RA patients. At the molecular level, biochemical assays and crystallography showed the mechanisms of action of Takinib on TAK1. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-α-induced cell death, with general implications for cancer and autoimmune disease treatment.
Takinib, a selective TAK1 inhibitor, broadens the therapeutic efficacy of TNFα inhibition for cancer and autoimmune disease
Emily R. Derbyshire(1), Timothy A. J. Haystead(1), Kenneth D. Westover(2)
Added on: 10-30-2021
New protocol to generate tumor-recognizing T cells with potentially less side-effects
2017
Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Fueled by impressive clinical results, adoptive T-cell therapy (ACT) is gaining more and more momentum in the battle against hematologic malignancies and solid tumors although it has also been associated with serious side effects. In the present study, the researchers aimed at establishing a protocol to expand and transiently transfect with mRNA a particular subset of T cell called γ/δ which may have fewer side effects. T cells were obtained from healthy donors and expanded ex vivo. The mRNA coding for an antibody specifically recognizing cancer cells was introduced; then receptor expression, antigen-specific cytokine secretion, specific cytotoxicity were analyzed in vitro. The study establishes a protocol adaptable to GMP for the expansion of γ/δ T cells and their subsequent RNA-transfection with tumor-specific TCRs or CARs. Given the transient receptor expression, the reduced cytokine release, and the equivalent cytotoxicity, these γ/δ T cells may represent a safer source of adoptive T-cell therapy.
RNA-transfection of γ/δ T cells with a chimeric antigen receptor or an α/β T-cell receptor: a safer alternative to genetically engineered α/β T cells for the immunotherapy of melanoma
Niels Schaft
Added on: 09-20-2021
Signaling mechanisms of disrupted lumen formation in breast cancer cells
2017
Beckman Research Institute of City of Hope, Duarte, USA
The lumen formation of breast cancer cells can be restored by recovering CEACAM1 expression. SASH1 was identified as one of the top up-regulated genes during lumen restoration and was found to be critical in lumen formation. Here, human breast cancer cells transfected with CEACAM1 were grown in 3D cultures to assess the signalling mechanisms of SASH1-dependent lumen formation. The results showed that in cells with interference RNA for SASH1, DLK1 was similarly downregulated as SASH1. Additionally, the inhibition of DLK1 in CEACAM1-expressing breast cancer cells also disrupted the lumenogenesis. Furthermore, DLK1 inhibited NOTCH1 signalling and, when using other NOTCH inhibitors, lumen formation was also hindered. Overall, the researchers demonstrate that lumen formation dependent on CEACAM1 is regulated through the NOTCH1 signalling pathway and points to NOTCH1 as a potential target that acts as a tumor-promoter through its dysregulation in cancer.
The adaptor SASH1 acts through NOTCH1 and its inhibitor DLK1 in a 3D model of lumenogenesis involving CEACAM1
John E Shively
Added on: 10-31-2021
Signalling mechanisms of lumen formation in breast cancer
2017
Beckman Research Institute of City of Hope, Duarte, USA
During cancer development, gene expression patterns change in cells undergoing transformation. In human breast tissue, there is a loss of lumenal expression of the CEACAM1 gene in the early stages of breast cancer. Some human breast cancer cell line cells regain the capacity of forming lumens when they are transfected with CEACAM1. Here, human breast cancer cells transfected with CEACAM1 are cultured in 3D and treated with a Jak2 inhibitor in order to elucidate the signalling mechanisms of the post-transfection gain of function. The results showed that lumen formation was hindered, probably driven by the inhibition of a set of genes downregulated in these cells. Furthermore, the selective downregulation of several of these genes blocked lumen formation. One of these genes, already described to be involved in mammary morphogenesis, was able to restore lumen formation when transfected in human breast cancer cells that lack CEACAM1 expression. Overall, the researchers suggest that lumenal formation involve several genes co-regulated with CEACAM1 and that modulation of some of these genes expression can recover some of the homeostatic functions of human breast cancer cells.
ETS transcription factor ELF5 induces lumen formation in a 3D model of mammary morphogenesis and its expression is inhibited by Jak2 inhibitor TG101348
John E Shively
Added on: 10-31-2021
Virtual screening method to discover tumor escape inhibitors
2017
Jilin University, Jilin, China(1)
Second Military Medical University, Shanghai, China(2)
Second Military Medical University, Shanghai, China(2)
Tumor escape is a hallmark of cancer, which brings many difficulties and troubles in cancer therapy. Indoleamine 2,3-dioxygenase 1 (IDO1) plays an important role in the immune escape of tumors, although it has emerged as a promising target for cancer therapy there are still very few drugs developed. In the present study, the researchers have designed a novel high throughput virtual screening to
search for potential IDO1 inhibitors. The screening method was used to screen commercially available compounds and identified some candidates with inhibition activity. Some of the compounds may serve as interesting starting points for future chemistry elaboration. The screening method was validated as a tool to be employed in the discovery of IDO1 inhibitors.
A novel high throughput virtual screening protocol to discover new indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors
Qing Yang(1), Yunlong Song(2)
Added on: 07-27-2021
3D model to study drug resistance of breast cancer cells
2017
Universidad de Buenos Aires, Buenos Aires, Argentina
Breast cancer stem cells that express HER2 can develop resistance to Trastuzumab. Recently, it was shown that breast cancer cells cultures as spheroids in a 3D environment developed autophagy and apoptosis, which induced drug resistance in HER2 overexpressing cells. Here, human mammary adenocarcinoma cells were cultured in 3D under hypoxic conditions. The results showed that culturing breast cancer cells in adverse conditions modulated the response to Trastuzumab. Moreover, in HER2+ cells, there was an increase in the breast cancer stem cell population. The 3D environment determined the expression of HER2 in breast cancer spheroids, where treatment with Trastuzumab induced the acquisition of resistance and the increase of the number of cancer stem cells, which had higher HER2 expression. Contrary, cells with low HER2 expression showed more sensitivity to Trastuzumab and decreased the number of cancer stem cells. Overall, the researchers show a link between 3D structures and the modulation of breast cancer stem cell population and HER2 expression which, in turn, regulates the response to Trastuzumab.
Breast cancer stem cells are involved in Trastuzumab resistance through the HER2 modulation in 3D culture
Gabriel L Fiszman
Added on: 10-08-2021
Affinity-based drug delivery with hydrogel
2017
Leiden University, Leiden, Netherlands
The study describes the design and production of a drug delivery scaffold based on hydrogels. All the gels are stable for more than 25 days and have tunable gelation times. Additionally, the hydrogels can efficiently deliver doxorubicin for over 7 days in a constant manner. Also, in cell viability tests, these hydrogels show to be biocompatible and deliver doxorubicin to human breast cancer cells. Overall, this system can be an important advance in drug delivery strategies.
Dual-crosslinked human serum albumin-polymer hydrogels for affinity-based drug delivery
Roxanne E Kieltyka
Added on: 07-29-2021
Human lung cell model with an air-liquid-interface in a reactor for toxicity testing
2017
Cultex Technology, Hanover, Germany
Human lung epithelial cells obtained during surgery are cultivated on a special membrane, over a nutrient medium. From the other side the cells are exposed to aerosols, directed over their surface. This simulates an air-liquid interface similar to that of the human lung. Via the exposure modules, these cell cultures can be vital for weeks. The exposure module directs a substance-bearing air stream over the cells, which is aspirated via a vacuum pump so that a continuous flow is created. This model enables the analysis of acute and chronic toxicity of substances, as well as of the lung cell repair mechanisms.
Improvement of the CULTEX® exposure technology by radial distribution of the test aerosol
Michaela Aufderheide
Michaela Aufderheide et al. Experimental and Toxicologic Pathology 2017 [583]
Cultex Technology [584]
Added on: 04-21-2020
Microfluidic device to investigate biophysical cues in cancer progression
2017
Binghamton University, Binghamton, USA
Fibroblasts are one of the stromal cell types that have a key role in cancer progression. Activated fibroblasts can come from endothelial cells undergoing a process of transformation into mesenchymal cell-like cells known as endothelial-to-mesenchymal transition. Low and oscillatory shear stresses have been shown to be relevant in metastasis through specific changes in cytoskeleton proteins, which can be relevant for stromal cells transformation. Here, a 3D microfluidic device with human endothelial cells was developed for investigating the impact of steady low shear stress and changes in the extracellular matrix properties on the endothelial-to-mesenchymal transition. The results showed that extracellular matrix composition and shear stress can regulate the endothelial-to-mesenchymal transition. Furthermore, when including 3D spheroids with human breast cancer cells in the device, it was elucidated that shear stress could also regulate the spheroid size and that cancer cell-related properties are induced by activated fibroblasts derived from cells undergoing endothelial-to-mesenchymal transition. Overall, the researchers present a new microfluidic platform that allows the investigation of the influence of biophysical cues of the tumor microenvironment in cancer-related processes and the mechanisms underlying them.
The role of shear stress and altered tissue properties on endothelial to mesenchymal transformation and tumor-endothelial cell interaction
Gretchen J Mahler
Added on: 10-19-2021
Nasopharyngeal carcinoma models to test the efficacy of immunotherapies
2017
Southern Medical University, Shenzhen, China
Relapse and metastasis of nasopharyngeal carcinoma are presumably attributed to cancer stem cells. In recent years, chimeric antigen receptor (CAR) modified immune effector cells have been shown to have impressive antitumour efficacy. Nasopharyngeal carcinoma models based on patients cells formed into spheroids are generated to use the efficiency of a novel immunotherapy based on CAR technology.
5T4-specific chimeric antigen receptor modification promotes the immune efficacy of cytokine-induced killer cells against nasopharyngeal carcinoma stem cell-like cells
Kaitai Yao
Added on: 07-01-2021
Novel microfluidic 3D model to study metastasis mechanisms
2017
Chinese Academy of Sciences, Beijing, China(1)
Chongqing University, Chongqing, China(2)
Chongqing University, Chongqing, China(2)
The study describes the development of a new multicellular hydrogel-based microfluidic 3D model seeded with human breast epithelial cells and human breast cancer cells. When seeding the epithelial cells with human breast cancer cells, their normal self-organization was impeded. This model brings new insights into the possible mechanisms of disruption of luminal structures. It also has the potential to be used in high-throughput applications to study complex multicellular interactions in the tumor microenvironment.
A novel 3-D bio-microfluidic system mimicking in vivo heterogeneous tumour microstructures reveals complex tumour–stroma interactions
Zhongcan Ouyang(1), Fangfu Ye(1), Liyu Liu(2)
Added on: 07-29-2021
Scaffold biofabrication for 3D culture of breast cancer stem cells
2017
University of Girona, Girona, Spain
Biofabrication of polycaprolactone scaffolds using electrospinning 3D-printing technique was used to improve human breast cancer stem cell culture. Using this method it is possible to increase the mammosphere formation and cell proliferation, indicating enrichment of cancer stem cells. Thus, this technique could be used to improve modelling of breast cancer stem cells and the development of new therapeutic strategies.
Electrospinning parameters selection to manufacture polycaprolactone scaffolds for three-dimensional breast cancer cell culture and enrichment
Joaquim Ciurana, Teresa Puig
Added on: 07-23-2021
3D microfluidic device to investigate metastasis mechanisms
2017
Sun Yat-Sen University Cancer Center, Guangzhou, China
Collective cell migration towards surrounding tissues is the first step of metastasis and an important obstacle for cancer therapy efficiency. However, the mechanisms behind this process remain elusive and in vitro models fail to recapitulate it in a real-time manner. Here, a 3D microfluidic model of human breast cancer cells is developed to recapitulate cell invasion by establishing a gradient of fetal bovine serum. The results showed that cancer cells adopted a collective movement to invade the extracellular matrix. Furthermore, leading cells had an increased expression of Aurora kinase family protein and, when inhibited, it was possible to disrupt the collective cohort formation. In this study, the researchers develop a 3D model that can reliably recapitulate some aspects of collective cell invasion and shows to be useful to study the mechanisms underlying this process, which could elucidate new potential therapeutic targets to block metastasis.
Inhibition of AURKA kinase activity suppresses collective invasion in a microfluidic cell culture platform
Quentin Liu
Added on: 10-12-2021
Mathematical model of immunomodulated tumor growth predicts responsiveness to immunotherapy
2017
Center of Cancer Systems Biology, Boston, USA
Immune response can both stimulate and inhibit tumor growth. The interplay between these competing influences of the immune system has complex implications for tumor development, cancer dormancy, and immunotherapies. The study builds a mathematical model able to predict non-intuitive yet clinically observed patterns of immunomodulated tumor growth. It may provide a means to help classify patient response dynamics to aid the identification of appropriate treatments exploiting immune response to improve tumor suppression, including the potential attainment of an immune-induced dormant state.
Modeling the dichotomy of the immune response to cancer: cytotoxic effects and tumor-promoting inflammation
Philip Hahnfeldt
Added on: 07-06-2021
Pathways monitored in prognostic signature of breast cancer subtypes
2017
Toronto General Research Institute—University Health Network, Toronto, Canada(1)
University of Toronto, Toronto, Canada(2)
University of Toronto, Toronto, Canada(2)
Validation in human breast tumor is performed in samples of a 17-gene prognostic signature for HER2 enriched tumor-initiating cells. The main objective of this study is to identify the biological pathways that monitor the prognostic genes. With a series of computational methods and human tumor samples, it is shown that the main pathways involved correspond to cell proliferation, immune response and cell migration. Additionally, it identifies substitutes and 6 core genes that would facilitate the clinical implementation of this method.
Identification of cell proliferation, immune response and cell migration as critical pathways in a prognostic signature for HER2+:ERα- breast cancer
Jeffrey C Liu(1), Eldad Zacksenhaus(2)
Added on: 08-01-2021
Peptides tested in vitro to block cancer-related receptor
2017
University Hospital of Lausanne, Lausanne, Switzerland(1)
University of Gdansk, Gdansk, Poland(2)
University of Gdansk, Gdansk, Poland(2)
Antibody-based immune-checkpoint blockade therapy is a major breakthrough in oncology, leading to clinical benefits for cancer patients. Among the growing family of inhibitory receptors, the B and T lymphocyte attenuator (BTLA), is a promising target for immunotherapy. In the present study, the researchers used the previously published crystal structure of BTLA to design and analyze the capacity of several peptides to block the ligation between BTLA and its ligand. The researchers demonstrated in vitro that one of the designed peptides could block the interaction between BTLA and its ligand although the effect was partly due to an artefact originating from the presence of cysteine residues in the peptide. The study concludes that extreme care should be put when developing blockers to avoid misleading artifacts.
Design of short peptides to block BTLA/HVEM interactions for promoting anticancer T-cell responses
Laurent Derré(1), Sylwia Rodziewicz-Motowidło(2)
Added on: 09-18-2021
3D model for microenvironment-dependent cancer treatments
2017
Istituto Italiano di Tecnologia, Genova, Italy(1)
Istituto Italiano di Tecnologia, Napoli, Italy(2)
Istituto Italiano di Tecnologia, Napoli, Italy(2)
Nanomedicine-based treatments for cancer therapy have been gaining popularity in recent years. However, classic 2D in vitro models have important limitations to replicate in vivo conditions, thus 3D models are emerging as reliable alternatives to better predict therapeutic efficiency. Here, a new 3D model was developed with a co-culture of human breast cancer cells and cancer-associated fibroblasts embedded in their own extracellular matrix to evaluate drug delivery techniques triggered by microenvironment factors. The results showed that there was an overexpression of MMP2 in these microtissues. Furthermore, recently validated MMP2 sensitive nanoparticles were able to release doxorubicin only at specific localisations, demonstrating the selectivity of this treatment and the validity of the model. Additionally, cell viability was only modulated by such drug delivery systems in the 3D setup. Overall, the researchers propose a new platform to explore nanoparticle-based strategies for cancer therapy and demonstrate that only 3D microtissues can faithfully predict in vivo tumour response.
3D tumor microtissues as an in vitro testing platform for microenvironmentally-triggered drug delivery systems
Daniela Guarnieri(1), Giorgia Imparato(2)
Added on: 11-02-2021
Biofabrication of a multicellular hydrogel-based model of cancer cell invasion
2017
Tulane University, New Orleans, USA
The study describes the development of a model based on a hydrogel scaffold using biofabrication. Human primary adipose cells from obese or normal patients were successfully combined with human breast cancer cells lines to study the impact of obesity in cancer cell invasion. Moreover, the transparency of the hydrogels gives the opportunity to easily monitor this model using microscopic methods. This model successfully integrates two cell types in a hydrogel microenvironment that allows studying cancer cell invasion of adipose tissue.
Laser direct-write based fabrication of a spatially-defined, biomimetic construct as a potential model for breast cancer cell invasion into adipose tissue
Douglas B Chrisey
Added on: 07-31-2021
3D human model for breast cancer drug screening
2017
University of South Florida, Tampa, USA
Despite recent improvements in breast cancer treatment, there are still severe limitations in their efficacy in eliminating breast cancer cells. This can lead to cancer relapse. Thus, better models are needed that accurately replicate the tumour microenvironment. Here, a 3D scaffold-based system with a culture of human breast cancer cells is developed to enrich breast cancer stem cells, increase drug resistance and recapitulate hypoxic tumour environments. The results show that this model could be used to screen several FDA-approved drugs and identify actinomycin D as a potential anti-breast cancer drug. Furthermore, it was revealed that actinomycin D depleted the breast cancer stem cell population from the model through the down-regulation of SOX2, which impeded the progression of the tumour. Overall, the researchers present a 3D platform to better reproduce tumour microenvironments and enhance the translationality of in vitro drug screening for better success rates in breast cancer therapy.
Actinomycin D down-regulates SOX2 expression and induces death in breast cancer stem cells
Subhra Mohapatra
Added on: 10-15-2021
A multicellular 3D model of the human breast duct
2017
Queen Mary University of London, London, United Kingdom
The study describes the development of a 3D model to understand the interactions between myoepithelial and luminal cells in breast cancer. HER2-inducible human primary myoepithelial and luminal cells were combined in collagen gels and were able to recapitulate in vitro the physiological bilayer structures. Inducing the expression of HER2 led to robust luminal filling, recapitulating ductal carcinoma, that could be blocked by using the drug Trastuzumab. In summary, this model can recreate the interactions between myoepithelial and luminal cells in the early stages of breast cancer development, having the potential to be a powerful drug discovery platform.
A 3D in vitro model of the human breast duct: a method to unravel myoepithelial-luminal interactions in the progression of breast cancer
Richard P Grose, Edward P Carter
Added on: 07-18-2021
Ex vivo enrichment of anti-cancer immune cells from donors
2017
Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
Adoptive immunotherapy using cytokine-induced killer cells (CIK) have been used in the clinic for a variety of malignant tumors. However, the preparation of CIK cells is heterogeneous and this affects the therapeutic efficacy. In the present study, the researchers report the enrichment and expansion of a particular subset of CIK cells from donors. The cells were characterized using flow cytometry and their cytotoxic potential was assessed in vitro against cancer cell lines. Sequencing analysis determined a preference of the CIK for a particular receptor present in ovarian cancer cells. The results suggest that transplantation of ex vivo enriched and expanded CIK cells may provide a novel avenue of targeted therapy for ovarian cancer.
Phenotypic characterization and anticancer capacity of CD8+ cytokine-induced killer cells after antigen-induced expansion
Yilin Cao, Wenjie Zhang
Added on: 09-18-2021
In vitro model of muscle cancer used to study immune response following treatment
2017
CNB-CSIC, Madrid, Spain
Bacillus Calmette-Guerin (BCG) is well known to be a potent enhancer of the immune response and as such has been used as a therapy for patients with high-risk non-muscle-invasive bladder cancer. However, the detailed mechanisms of action of this therapy are not well understood. In the present study, the researchers generated an in vitro model of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG to study the immune response. Natural Killer (NK) cells were especially present and active and this in vitro data was then confirmed in tissues from patients treated with BCG and not with another type of treatment. These observations suggest that activation of NK cells may be an important component of the anti-tumor immune response triggered by BCG therapy in bladder cancer.
Characterization of a human anti-tumoral NK cell population expanded after BCG treatment of leukocytes
Mar Valés-Gómez
Added on: 07-29-2021
Modifications of progesterone receptors are involved in expression of breast cancer stem cell-associated genes
2017
University of Minnesota, Minneapolis, USA
Phosphorylation events of progesterone receptors (PR) have a major impact on their activity in breast cancer. In this study, they first screen modified PR in human breast cancer explants and make an assay with luminal 3D breast cancer model T47D treated with progestin or antiprogestins. The authors found that most explants had phosphorilation modifications and that these were associated with invasive lobular carcinoma and with the expression of genes that enable the maintenance of cancer stem cell fate.
Posttranslationally modified progesterone receptors direct ligand-specific expression of breast cancer stem cell-associated gene programs
Carol A. Lange
Added on: 07-02-2021
AKR1B10 is a pro-carcinogenic and pro-metastatic factor in breast cancer
2017
University of South China, Chenzhou, China
AKR1B10 has been observed to be highly expressed in different types of cancer. However, the mechanisms underlying its role in breast cancer remain unknown. Here, patient samples and human breast cancer cells were used to investigate the role of AKR1B10 expression in cancer-related features. The results showed that AKR1B10 expression was increased in cancer samples and correlated positively with the severity of the disease. Moreover, human breast cancer cells overexpressing AKR1B10 had increased metastatic abilities. Additionally, ERK signalling was identified as the downstream effector of AKR1B10-induced migration and invasive behaviour through the promotion of MMP2 and vimentin expression. Finally, the MEK inhibitor PD98059 could block the effects of AKR1B10 signalling mechanisms. Overall, the researchers demonstrate the pro-carcinogenic and pro-metastatic role of AKR1B10 and elucidate the signalling pathway that mediates its activity.
AKR1B10 promotes breast cancer cell migration and invasion via activation of ERK signaling
Di-Xian Luo
Added on: 10-31-2021
Comparative study of tumor 3D modelling methods
2017
University of Massachusetts Amherst, Amherst, USA
Despite recent advances, better in vitro models are needed to improve our understanding of cancer progression and increase the translationality of new findings. Multicellular tumor spheroids are a popular choice for 3D tumor modelling because they capture many of the features present in vivo. However, there is a lack of reproducibility in the observations obtained through the different techniques used to build these 3D models. Here, human breast, prostate and ovarian cancer cells are used in hydrogel, microwells or suspension culture set-ups to compare their behaviour and characterize the different modelling techniques. The results showed that the different approaches induced different reliance on genes involved in cell-cell or cell-matrix interactions. Moreover, drug sensitivity depended on the type of cell growth induced by the model setup. Finally, a human ovarian cancer cell line culture in the hydrogel setup was found to have the most reproducible drug response when compared to patient cells, despite being the most time and cost-intensive. Overall, the researchers demonstrate that the methods used to build 3D models have an influence on the outcome of the experimental procedures performed and have to be carefully chosen depending on the applications required.
Comparative study of multicellular tumor spheroid formation methods and implications for drug screening
Shelly R Peyton
Added on: 10-04-2021
Leukemic cell lines and patients cells to test efficiency of immunotoxins
2017
Indian Institute of Technology Madras, Chennai, India
The study describes a modern therapeutic approach to target chemotherapy-resistant leukemic stem cells (LSCs) to prevent disease relapse. In the present study, the researchers reported for the first time a novel immunotoxin conjugate peptide to specifically target leukemic stem cells. The immunotoxin was tested in a total cell population and LSCs isolated from human leukemic cell lines available from the National Center for Cell Science in Pune, India. Leukemic patients' cells were also used for testing. The developed immunotoxin induced potent cytotoxicity in leukemic cells from cell lines and patient samples. Additionally, the immunotoxin could induce apoptosis also in resistant cell lines, relapsed patient samples and LSCs isolated from leukemic patients and cell lines. Further development of the immunotoxin could prove valuable in a multi-targeted approach to tackle drug resistant leukemia.
CD25 targeted therapy of chemotherapy resistant leukemic stem cells using DR5 specific TRAIL peptide
Rama Shanker Verma
Added on: 07-27-2021
MMP-8 is essential for tumor suppressor function of myoepithelial cells
2017
Queen Mary University of London, London, United Kingdom
Under normal conditions, myoepithelial cells have a tumor-suppressor role in the breast. However, in ductal carcinoma in situ, they gain a tumor-promoter behaviour. One of the changes described in these transformed cells is the loss of expression of MMP-8. Here, MMP-8 expression was modulated in normal and ductal carcinoma in situ associated myoepithelial cells to investigate how it affects cancer-related features. The results confirmed a loss of expression of MMP-8 in cancer-related cells. Across all the assays performed in this study, the overexpression of MMP-8 could reduce cancer-related features, while the knock-down of MMP-8 induced cancer cell characteristics, with special emphasis on processes related to cell migration and invasion. Finally, the expression of MMP-8 correlated negatively with the presence of invasion in ductal carcinoma in situ samples from patients. Overall, the researchers confirm that MMP-8 is essential for the tumor-suppressor function of myoepithelial cells and its loss is related to increased metastatic behaviour, making it a potential biomarker for the risk assessment of ductal carcinoma in situ progression.
Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function
J Louise Jones, Michael D Allen
Added on: 10-21-2021
Photon-counting spectral mammography for classification of breast cancer
2017
U.S. Food and Drug Administration, Silver Spring, USA
Breast cancer classification using photon-counting spectral mammography is validated through a simulation of breast calcifications. When applied to the simulated events, this method was able to discriminate between different types of microcalcifications. Therefore, the results support the potential of this method as a non-invasive technique to improve early breast cancer diagnosis.
Investigating the feasibility of classifying breast microcalcifications using photon-counting spectral mammography: a simulation study
Bahaa Ghammraoui
Added on: 07-28-2021
Stimulation of T cells with tumor-specific peptide to develop immunotherapy
2017
University of Tübingen, Tübingen, Germany
The discovery of antigens specific to tumor cells is of crucial importance to develop efficient immunotherapy against cancer. Recent genome sequencing has uncovered a recurring somatic and oncogenic driver mutation of the Toll-like receptor adaptor protein MYD88 with the potential to be a specific antigen used for immunotherapy. Using in silico predictions, the researchers identified different MYD88L265P peptides and tested them for their stimulation capacity on T cells obtained from diseased patients. Cytotoxic capacity after stimulation was tested in vitro. The study shows the potential of stimulation to generate tumor-specific immunotherapy.
HLA class I-restricted MYD88 L265P-derived peptides as specific targets for lymphoma immunotherapy
Alexander N. R. Weber
Added on: 07-29-2021
3D model to investigate mechanisms of cancer cell invasion
2017
PSG College of Technology, Coimbatore, India
Breast cancer metastasis is a complex process and current models poorly reproduce it in vitro. This hinders the investigation of the mechanisms underlying it and the development of therapeutic strategies. Thus, better in vitro models are needed, and 3D platforms have had a growing interest in recent years. Here, a gelatine nanofiber matrix was biofabricated and coated with collagen to mimic connective tissues and be used as a platform to culture human breast cancer cells. The researchers performed a physical characterization of the nanofiber matrix and confirmed its biocompatibility to culture human breast cancer cells. Furthermore, estrogen and progesterone were able to induce epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition, respectively, and increased the expression of metastasis-related genes. Additionally, this was confirmed by the enhanced invasive behaviour of cancer cells. Overall, in this study, a new biocompatible 3D platform is presented to investigate the mechanisms underlying cancer cell invasion in vitro.
An in vitro 3D model using collagen coated gelatin nanofibers for studying breast cancer metastasis
C Sabarinath
Added on: 10-26-2021
Coupling of image analysis platform to breast cancer models
2017
Ewha Womans University, Seoul, South Korea(1)
Ewha Womans University School of Medicine, Seoul, South Korea(2)
Ewha Womans University School of Medicine, Seoul, South Korea(2)
Improvement of mammosphere assays is achieved by coupling in vitro models of human breast cancer cells to a medium-throughput imaging workflow and automated analysis. Using this method, it was possible to screen a library of several protein kinase inhibitors to further do an in-depth analysis of the mechanisms of the selected drugs in human breast cancer stem cells. Several signalling pathways are identified as targets to tackle several properties of cancer stem cells. This new automated platform has shown a great potential for drug screening of inhibitors of breast cancer stem cell activity.
Screening of breast cancer stem cell inhibitors using a protein kinase inhibitor library
Eok-Soo Oh(1), Duk-Hee Kang(2)
Added on: 07-22-2021
Deeper understanding of cellular interaction between neutrophils and blood vessels
2017
University of Minnesota, Minneapolis, USA
A gel scaffold is constructed on a microfluidic device in microchambers, in which stable chemical gradients can be generated so that migration is stimulated in cells; these can also be quantified. A new finding is that the migration of neutrophils reduces the effect of a drug that inhibits endothelial migration.
It shows the complicated cellular interactions between endothelial cells and neutrophils: Endothelial migration highly sensitively regulates neutrophil migration, while the presence of neutrophils stabilizes the structures required for endothelial migration.
Endothelial cell migration is an essential component of angiogenesis, therefore it is involved in wound healing, tissue growth and reproductive organ development, among other things. In addition, endothelial cell migration could play a crucial role in many diseases characterized by over-profiling of blood vessels, such as cancer, arthritis, atherosclerosis and cardiovascular diseases.
The system enables a deeper understanding of the dynamic cellular interaction between neutrophils and endothelial cells and the pathogenesis of diseases.
A versatile microfluidic platform for the study of cellular interactions between endothelial cells and neutrophils
Christy Haynes
Added on: 05-29-2020
Drug testing on a new microchip-based model
2017
Ege University, Izmir, Turkey
The goal of this study is to test the response of human breast cancer cells and healthy mammary epithelial cells to carnosic acid and doxorubicin in a microchip model. Three models are compared: 2D monolayer culture, 3D culture and the microchip culture. It was found that cell viability was higher in the microchip model. Also, both therapeutic molecules had specific responses to different cancer cell lines and those responses were dependent on their chemical structure. Overall, this model shows to be a promising tool in the study of cancer therapeutics and allows the inclusion of structural complexity parameters into "in vitro" modelling.
Cytotoxic responses of carnosic acid and doxorubicin on breast cancer cells in butterfly-shaped microchips in comparison to 2D and 3D culture
Ozlem Yesil-Celiktas
Added on: 08-02-2021
Engineered T cells used in clinical study to treat nasopharyngeal carcinoma
2017
QIMR Berghofer Medical Research Institute, Brisbane, Australia(1)
The University of Hong Kong, Hong Kong, Hong Kong SAR of China(2)
The University of Hong Kong, Hong Kong, Hong Kong SAR of China(2)
The extension of adoptive T cell therapy to solid cancers remains a significant challenge. In this study, the researchers performed a clinical study to test a new type of engineered autologous T cell to specifically treat different degrees of nasopharyngeal carcinoma (NPC) patients. Cells were taken from the patients, modified ex vivo in GMP conditions and delivered back to the patients. Tolerability, safety and efficacy, including progression-free survival and overall survival, were evaluated. Overall, the clinical outcomes were promising and further suggest a potential role for this approach as a consolidation treatment following first-line chemotherapy.
Pre-emptive and therapeutic adoptive immunotherapy for nasopharyngeal carcinoma: Phenotype and effector function of T cells impact on clinical response
Rajiv Khanna(1), Dora Kwong(2)
Added on: 07-29-2021
High-throughput drug screening device for cancer stem cells
2017
Göteborgs Universitet, Göteborg, Sweden
Cancer stem cells are a major cause of breast cancer relapse. However, there are no treatments that efficiently target those cells. Thus, there is an urgency in identifying novel treatments that specifically modulate cancer stem cells. Here, a robotic platform was developed to perform high-throughput drug screening based on mammosphere and anoikis resistance assays with human triple-negative breast cancer cells. The assay was validated by comparing the data generated by the developed platform and the classical manual protocols. The results show that there were no significant differences in the data generated with both methods. Moreover, with this new workflow, 3 out of 989 FDA-approved compounds were identified to target breast cancer stem cells. Overall, the researchers present a new device that could potentially boost cancer stem cell drug screening and identify highly efficient compounds to be used as adjuvant treatments.
Robotic mammosphere assay for high-throughput screening in triple-negative breast cancer
Göran Landberg
P A Fitzpatrick et al. SLAS DISCOVERY: Advancing the Science of Drug Discovery 2017 [636]
EURL ECVAM [637]
Added on: 10-27-2021
Mathematical model to assess a combination of cancer therapies
2017
Winthrop University, Rock Hill, USA
A recent theory for tumor growth suggests that a small population of cancerous cells known as cancer stem cells have stem cell-like qualities. In the present study, the researchers developed a mathematical model of the effectiveness of immunotherapy and chemotherapy for the treatment of tumor cells and cancer stem cells. The researchers present conditions on treatment parameters to guarantee a globally attracting tumor clearance state. Further work on this model could incorporate healthy cells and monitor the detrimental effect chemotherapy has on the overall health of a patient. Also in the future, an updated model could consider different submodels for possible cancer persistent states or other specific chemotherapy and immunotherapy agents.
Global dynamics of a colorectal cancer treatment model with cancer stem cells
Kristen Abernathy
Added on: 07-27-2021
Computational method to diagnose breast cancer
2017
Northwest University, Xi’an, China
The study describes the development of a computational method to detect clustered microcalcifications from mammograms for early diagnosis of breast cancer. Based on a series of algorithms, this method allows classifying the samples in lesioned or normal breast tissues. When tested with synthetic and real samples, it reduces false-positive rates while maintaining the true positive rate. This computational tool can potentially be useful for the early diagnosis of breast cancer.
Grouped fuzzy SVM with EM-based partition of sample space for clustered microcalcification detection
Jun Feng
Added on: 08-01-2021
Ex vivo characterization of immune cells from lung cancer patients
2017
Houston Methodist Research Institute, Houston, USA(1)
Sun Yat-sen University, Guangzhou, China(2)
Sun Yat-sen University, Guangzhou, China(2)
Autologous tumor-infiltrating lymphocytes (TILs) is a new effective cancer therapy but the application is still limited in many solid tumors. In the present study, the researchers analyzed by flow cytometry cells obtained from lung cancer patients the characteristics and subtypes of immune cells. To further analyze their functions, the researchers stimulated TILs from patients to examine cytokine production and demonstrate strong cytokine production. One subset of TILs looks promising for adoptive cell therapy in human lung cancer.
The characteristics of naive-like T cells in tumor-infiltrating lymphocytes from human lung cancer
Rong Fu Wang(1), Hai Hong(2)
Added on: 07-29-2021
Role of microRNA-645 in metastasis
2017
Jilin Cancer Hospital, Changchun, China
Several microRNAs have been described to have a crucial role in cancer regulation. Despite having anti-cancer activity in some tumors, the role of microRNA-645 in breast cancer remains unclear. Here, human breast cancer samples and human cancer cell lines were used to investigate the role of microRNA-645 in breast cancer cell metastasis. The results showed that microRNA-645 was upregulated in breast cancer tissue from patients. Then, the downregulation of microRNA-645 inhibited metastatic features in breast cancer cells. Moreover, a bioinformatic analysis identified DCD2 as the target gene of microRNA-645 and its inhibition lead to tumor suppression activity similar to the downregulation of microRNA-645. Overall, the researchers describe the mechanisms of microRNA-645 which lead to the identification of a novel target for tumor suppression and a potential new biomarker candidate for breast cancer.
Downregulation of microRNA-645 suppresses breast cancer cell metastasis via targeting DCDC2
Ke Liu
Added on: 10-30-2021
3D multicellular model combining endothelial and breast cancer spheroids
December 2016
Drexel University, Philadelphia, USA
A multicellular 3D model is developed by combining human endothelial spheroids and human breast cancer spheroids to mimic breast tumor interactions with vascular structures. The combination of both models is able to recreate a metastatic microenvironment that allows breast epithelial tumors to grow and migrate through the vascular-like structures, demonstrating the potential of this model to study the physiology of these cell-cell interactions and metastasis.
Vascular endothelial–breast epithelial cell coculture model created from 3D cell structures
Alisa Morss Clyne
Added on: 07-14-2021
Genomic analysis of estrogen receptor-associated breast cancer
December 2016
University of Pittsburgh, Pittsburgh, USA(1)
University of Pittsburgh Cancer Institute, Pittsburgh, USA(2)
University of Pittsburgh Cancer Institute, Pittsburgh, USA(2)
Estrogen receptors are known to be critical for breast cancer through DNA binding mechanisms, leading to transcriptomic and phenotypic changes. Thus, single nucleotide variants in estrogen receptor binding sites might be involved in disease progression. Here, a computational analysis to identify single nucleotide variants in estrogen receptor binding sites is performed using chromatin immunoprecipitation sequencing data from different breast cancer models and further validated with human breast cancer cells to identify allele-specific binding. The analysis identified an intronic single nucleotide variant predicted to increase estrogen receptor binding and was experimentally validated. Furthermore, 17 regulatory single nucleotide variants correlated with expression of adjacent genes in estrogen receptor-associated breast cancer, from which GSTM1 promoter was the top candidate and showed to be correlated with higher expression of GSTM1 in estrogen receptor-associated tumors and better outcome in patients. Overall, the researchers establish a computational pipeline that can be used to investigate and elucidate key single nucleotide variants that can potentially regulate target genes contributing to the outcome of breast cancer in patients.
Non-coding single nucleotide variants affecting estrogen receptor binding and activity
Adrian V Lee(1), Steffi Oesterreich(2)
Added on: 10-12-2021
Method to isolate cancer stem cells
December 2016
Kermanshah University of Medical Sciences, Kermanshah, Iran
In this paper, it is shown that by using vincristine for 72 hours together with a suspension culture of human breast cancer cells is possible to obtain a highly pure culture of cancer stem cells. This is confirmed by immunofluorescence and gene expression of specific cancer stem cell genes. Also, the mammosphere formation assay shows an increased capacity of these isolated cells to form units. Therefore, the use of vincristine combined with cell suspension could be used as a method to isolate cancer stem cells.
Isolation of breast cancer stem cell from MDA-MB231 cell line using vincristine
Mozafar Khazaei
Added on: 07-31-2021
Synergistic therapy for breast cancer with miRNA and lipid nanoparticles
December 2016
Zhejiang University, Hangzhou, China
Cancer stem cells are a major obstacle in the treatment of breast cancer due to, among other things, their drug resistance capabilities. However, microRNA-200c has been described to reduce the expression of class III beta-tubulin, which recovers sensitivity to microtubule-targeting drugs. Here, a combination of microRNA-200c and paclitaxel mediated by lipid nanoparticles is used to target breast cancer stem cells in mammospheres generated with human breast cancer cells. The results show that the lipid nanoparticles protected microRNA-200c from degradation and had higher cellular uptake efficiency than other methods. Furthermore, the microRNA-200c could be efficiently released from the lipid complex inside the cell. Finally, the transfection of the microRNA-200c-lipid complex into breast cancer stem cells induced downregulation of class III beta-tubulin and enhanced paclitaxel-mediated cytotoxicity of breast cancer stem cells. Overall, the researchers develop a new drug release strategy to deliver microRNA-200c in target-specific areas that, when combined with chemotherapy, can induce cell death of breast cancer stem cells.
MicroRNA-200c delivered by solid lipid nanoparticles enhances the effect of paclitaxel on breast cancer stem cell
Fuqiang Hu
Added on: 10-30-2021
Vitamin D compounds modulate cancer stem cells
December 2016
The State University of New Jersey, Piscataway, USA
Triple-negative breast cancer remains one of the most problematic breast cancers to treat. Thus, preventive strategies might be a useful tool to impede cancer progression. A critical factor of cancer development and progression is cancer stem cells. In a previous study, vitamin D compounds were able to disrupt tumor behaviour of cancer stem cells. Here, a human triple-negative breast cancer cell line is used to produce 3D mammospheres and assess the effects of vitamin D compounds in breast cancer stem cells and differentiation in triple-negative breast cancer. The results showed that vitamin D compounds could reduce the mammosphere forming efficiency and decrease the expression of pluripotency markers. Moreover, these compounds also blocked the Notch signalling pathway involved in stem cell maintenance. Finally, treatment with vitamin D compounds induced myoepithelial markers expression and downregulation of luminal and breast cancer-associated markers. Overall, the researchers confirm that vitamin D compounds have the potential to be used in triple-negative breast cancer therapy to modulate breast cancer stem cells and prevent the development of the disease.
Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer
Nanjoo Suh
Naing Lin Shan et al. The Journal of Steroid Biochemistry and Molecular Biology 2017 [654]
EURL ECVAM [655]
Added on: 10-30-2021
3D model to reproduce tumor physiology
November 2016
Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
In this study, a 3D spheroid model is used combined with a HER2+ human breast adenocarcinoma cell line. This allows for better reproduction of the intercellular structures that avoid anti-cancer drug penetrance inside tumor structures. In this case, when using the immunotoxin 4D5scFv-PE40 in this model, the cytotoxicity was significantly lower than in monolayer 2D cultures, confirming that 3D structure properties play a key role in drug response. This model can be further used in drug testing to overcome the current limitations.
Spheroids of HER2-positive breast adenocarcinoma for studying anticancer immunotoxins in vitro
I V Balalaeva
Added on: 08-02-2021
Development of a web-based platform to help designing immunotherapy against cancer
November 2016
CSIR-Institute of Microbial Technology, Chandigarh, India
Identification of cancer-specific epitopes or neoepitopes from cancer genomes is one of the major challenges in the field of immunotherapy or vaccine development. Due to advancements in sequencing technology, the genomes of thousands of cancer tissues or cell lines have been sequenced. In the present study, the researchers developed an in silico platform (called Cancertope) for designing genome-based immunotherapy or vaccine against cancer cells. To do this, the researchers analyzed the mutational profile of 905-cancer cell lines and identified neoepitopes that can activate different arms of the immune system. The platform can be used to look for cancer antigens but can also be used in a personalized fashion to identify neoepitopes from the genomes of cancer patients. Cancertope is a web-based platform open for use by the scientific community.
A platform for designing genome-based personalized immunotherapy or vaccine against cancer
Gajendra P. S. Raghava
Added on: 09-17-2021
Immunocytochemistry on lung cancer patients tumours to assess response to therapy
November 2016
Yale University School of Medicine, New Haven, USA
PD-L1 is a transmembrane protein targeted by monoclonal antibody therapy targets in cancer. Yet, it has highly heterogeneous expression in tumours. In the present study, the researchers examined the expression by immunohistochemistry and quantitative immunofluorescence on tissues obtained from lung cancer patients and compared readings between pathologists. The results should allow for better assessment of the response to therapy.
Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer
David L Rimm
Added on: 07-28-2021
Importance of tumor microenvironment for immune response against cancer shown in patients tissues
November 2016
University of Otago, Dunedin, New Zealand
The growth and spread of colorectal cancer (CRC) can be prevented partially by T cells but tumor microenvironment may pose difficulties. In this study, the researchers aimed at determining if T cells functionality was different in tumor or non-tumor tissues of patients. Tissues were obtained from a large cohort of patients and were then analysed ex vivo. T cell populations were at different frequencies and different subtypes between tumor and non-tumor of the same patients. Further, the T cells infiltrating the tumor have an impaired proliferative ability compared non-tumor environment. The study confirms the TME is crucial to predict the effect of immune-modulatory therapies.
Functional impairment of infiltrating T cells in human colorectal cancer
Roslyn A. Kemp
Added on: 07-29-2021
Individualised cancer metabolic models
November 2016
University of Costa Rica, San José, Costa Rica
The study describes the development of a computational approach to predict cancer prognosis. The cancer-specific models are developed by combining existing general metabolic models with transcriptomic data. As a test, different expression datasets of breast cancer cell lines are used to generate 3 cancer-specific models and allow the description of specific metabolic signatures related to aspects of human breast cancer. This application can help in personalised cancer targets to improve cancer treatments.
A biocomputational application for the automated construction of large-scale metabolic models from transcriptomic data
R.A. Mora-Rodriguez, Edwin Baez-Villalobos
Edwin Baez-Villalobos et al. IEEE 36th Central American and Panama Convention (CONCAPAN) 2016 [664]
EURL ECVAM [665]
Added on: 07-29-2021
New 3D model to assess activity of immunotherapy agents against cancer
CompanyNovember 2016
Roche Innovation Center Zurich, Schlieren, Switzerland
To enable better assessment of cancer immunotherapy agents in vitro, a three-dimensional model based on human cells was developed. This model includes tumor cells, fibroblasts and immune cells to mimic the complexity of the tumor environment particularly regarding tumor–host interactions. This new 3D model is shown fit to assess drug targeting, efficient stimulation of immune cell infiltration, and specific elimination of tumor or fibroblast areas.
A novel three‑dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents
Marina Bacac
Added on: 07-01-2021
New 3D multicellular tumor-on-chip model for breast cancer
November 2016
Istituto Italiano di Tecnologia, Napoli, Italy
Tumor stroma activation has a key role in tumor progression. However, up to date, this is a feature of metastasis that has not yet been replicated in vitro. Thus, there is a need to generate new models that include the activation of tumor stroma to better understand the mechanisms underlying tumor epithelial invasion. Here, a novel model of breast cancer is proposed using a 3D multicellular tumor-on-chip with human breast cancer cells and a stroma compartment composed of a cell-assembled extracellular matrix. The results showed that it was possible to replicate a stromal activation both at the cellular and extracellular matrix levels, including the overexpression of key proteins during extracellular matrix remodelling. Furthermore, the stroma compartment allowed online monitoring with real-time multiphoton microscopy of different cellular processes occurring during stroma activation. Overall, the researchers propose a new 3D multicellular tumor-on-chip model that replicates stroma activation and that can be used to decipher the key mechanisms involved in tumor epithelial invasion in breast cancer.
An engineered breast cancer model on a chip to replicate ECM-activation in vitro during tumor progression
Giorgia Imparato
Added on: 10-03-2021
New potential drug test in a breast cancer cell model
November 2016
Ludwig-Maximilians-Universität Munich-Innenstadt, Munich, Germany
The researchers test galectin-1 in different proliferation and apoptotic assays of monolayer and 3D cultures of human breast cancer cell lines. Galectin-1 is able to inhibit proliferation and metabolic cell activity and induce apoptosis in those cells that have high levels of Thomsen-Friedenreich antigen. The study shows galectin-1 efficiency in 3D tumor microenvironments.
Binding of galectin-1 to breast cancer cells MCF7 induces apoptosis and inhibition of proliferation in vitro in a 2D- and 3D- cell culture model
Udo Jeschke
Added on: 07-11-2021
Potential synergistic effect of radiotherapy and immunotherapy shown in vitro on cancer cells
November 2016
National Institutes of Health, Bethesda, USA
Prostate cancer is one of the most prevalent malignancies among men worldwide. Castration-resistant prostate cancer (CRPC) has a high tendency to metastasize to bone. One treatment option for CRPC is a combination of radiotherapy and immunotherapy but it is currently unknown if radiation therapy can alter the phenotype of the surviving tumor cells in ways that render them more susceptible to cytotoxic T lymphocyte (CTL)-mediated attack. In the present study, the researchers exposed human prostate, breast, and lung carcinoma cells to sublethal doses of 223Ra radiotherapy in vitro. 223Ra significantly enhanced T cell-mediated lysis of each tumor type. Immunofluorescence analysis revealed that the increase in CTL killing was accompanied by augmented protein expression of molecules that are essential for efficient antigen presentation. The phenotypic changes observed after radiotherapy appear to be mediated by induction of the endoplasmic reticulum stress response pathway. By rendering tumor cells more susceptible to T cell-mediated lysis, 223Ra may potentially be effective in combination with various immunotherapies.
Sublethal exposure to alpha radiation (223Ra dichloride) enhances various carcinomas’ sensitivity to lysis by antigen-specific cytotoxic T lymphocytes through calreticulin-mediated immunogenic modulation
James W. Hodge
Added on: 09-19-2021
Predicton of resistance or sensitivity to oncolytic virus studied by gene expression profile in vitro on cancer cells
November 2016
Pusan National University, Yangsan, South Korea(1)
SillaJen, Inc., Busan, South Korea(2)
SillaJen, Inc., Busan, South Korea(2)
Oncolytic viruses (OVs) mediate tumor regression through selective replication in, and lysis of, tumor cells and induction of systemic anti-tumor immunity without damage to normal cells. Pexa-Vec is a cancer-specific and transgene-inserted oncolytic and immunotherapeutic vaccinia virus. As far as now, no studies have used Pexa-Vec to treat hematologic malignancies. In the present study, the researchers investigate the oncolytic effects of Pexa-Vec in vitro against lymphoid or myeloid cancer cell lines. Gene expression analyses were also conducted to determine the possible predictive gene changes in Pexa-Vec resistant cells compared with sensitive cells. These changes may enable clarify the characteristics of cancers resistant to Pexa-Vec. Interestingly, lymphoid malignant cells were shown to be resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec.
Gene expression profiling of hematologic malignant cell lines resistant to oncolytic virus treatment
Tae-Ho Hwang(1), Hyuk-Chan Kwon(2)
Added on: 09-19-2021
Scaffold influence in a 3D model of breast cancer metastasis
November 2016
University of Pittsburgh, Pittsburgh, USA
A 3D model is used to study the influence of scaffold properties in human breast cancer metastatic cells. When mixed in softer hydrogel scaffolds with hepatic tissue, metastatic cells were more prone to acquire dormant profiles and were more responsive to inflammatory stimuli, while hepatic cells were less pro-inflammatory. Additionally, dormant cells вев more responsive to certain doses of chemotherapy. This shows the potential improvements that this model can bring to personalized therapeutic strategies to target dormant metastatic breast cancer cells.
A liver microphysiological system of tumor cell dormancy and inflammatory responsiveness is affected by scaffold properties
Alan Wells
Added on: 07-29-2021
Biofabricated 3D matrix to model bone tissue
October 2016
The George Washington University, Washington, USA
Metastasis is a devastating step in cancer progression that leads to severe complications. Bone tissue is one of the first and most invaded tissues in breast cancer. Nowadays, the available in vitro models to study this pathological process are still poorly related to the in vivo conditions. Here, a bioprinted 3D biomimetic bone hydrogel-based matrix is used to culture human breast cancer cells and human fetal osteoblasts and bone marrow mesenchymal stem cells to investigate their interactions. It was possible to print hydrogel-based bone matrices with bone stromal encapsulated cells. The results show that the presence of bone cells enhanced the proliferation of human breast cancer cells and their levels of vascular endothelial growth factor, but the cancer cells had the contrary effect on bone cells proliferation and stemness. Overall, the researchers propose a new 3D bioprinted platform to study the effects of different cell types in bone tissue microenvironment, which could be a useful tool for human breast cancer research.
3D bioprinting a cell-laden bone matrix for breast cancer metastasis study
Lijie Grace Zhang
Added on: 10-15-2021
Drug to reveal immunotherapy target in tissues from prostate cancer patients
October 2016
University of Wisconsin, Madison, USA
Prostate cancer (PC) remains the most common cancer and the second leading cause of cancer-related death in men. Expanding cancer immunotherapies to a broader range of patients could be achieved through novel target identification and vaccine development. An ideal tumor antigen is one to which the immune system is naïve and whose expression can be persistently induced in tumor cells. One class of TAAs that meet these criteria are the cancer testis antigens (CTAs) which expression can be specifically increased using epigenetic modifying agents (EMAs). In the present study, the researchers wanted to determine the expression pattern and inducibility of CTAs in human PC. Expression patterns of 29 potentially immunologically relevant CTAs were evaluated in 5 PC cell lines. This expression pattern varied across different CTAs and was at least partially related to the androgen sensitivity of these cell lines. Human PC biopsies showed almost no expression of CTAs at baseline but it could be significantly induced following treatment with EMAs. Gene expression analysis of CTAs in circulating tumor cells further identified a subset of patients with metastatic PC that could benefit from vaccines targeting CTAs. These results identify a translational paradigm in which combining EMAs with CTA-targeted vaccines in patients with PC can enhance immune-mediated tumor lysis.
Inducible expression of cancer-testis antigens in human prostate cancer
Joshua M. Lang
Added on: 09-19-2021
In silico analysis of estrogen receptor alpha signaling pathway
October 2016
National University of Science and Technology, Islamabad, Pakistan
The construction of a discrete model is described to analyse the behaviour of estrogen receptor alpha-associated signalling pathways to understand some of the mechanisms that lead to breast cancer metastasis. The model was able to determine gene-gene interactions of different receptors that lead to inhibition of tumour suppressor genes, giving new insights to direct further research in the treatment of human breast cancer therapies.
Formal modeling and analysis of ER-α associated Biological Regulatory Network in breast cancer
Rumeza Hanif, Samra Khalid
Added on: 07-29-2021
MicroRNA identified as potential immunotherapy target from patients' tissues
October 2016
Dana-Farber Cancer Institute, Boston, USA
In colorectal cancer, the degree of infiltration of T lymphocytes has been associated with a favourable prognosis. MicroRNAs are small non-coding RNAs that epigenetically regulate diverse biological and pathologic processes, including immune response and tumor progression. The let-7 microRNA family has been shown to play an important role in host immunity. In the present study, the researchers examined let-7 miRNA expression in colorectal cancer tissues from two U.S.-nationwide prospective cohort studies. This analysis was correlated with imaging analysis of immune cell infiltration of the tumors. The study shows that a specific microRNA of the let-7 family is associated with suppressing antitumor immunity in colorectal cancer and suggests that it could be a potential target of immunotherapy.
MicroRNA let-7, T cells, and patient survival in colorectal cancer
Zhi Rong Qian, Shuji Ogino
Added on: 09-14-2021
Scaffold properties condition breast cancer cell activity
October 2016
IEIIT Institute, Genoa, Italy
Described is the development of a hydrogel scaffold to use 3D culture to model human breast cancer. Due to the culture in 3D conditions, a human breast cancer cell line shows properties that resemble better the in vivo conditions compared to 2D cultures. Also, the researchers found that there is a direct correlation between the elasticity of the hydrogels and proliferation and cluster formation, showing that cancer studies need more realistic models.
Microenvironment complexity and matrix stiffness regulate breast cancer cell activity in a 3D in vitro model
Silvia Scaglione
Added on: 07-12-2021
3D microfluidic platform to study cell invasion
2016
Arizona State University, Tempe, USA
Breast cancer is one of the most prevalent cancers in women. Invasion of surrounding tissues is one of the most critical steps to avoid the spread of the disease. However, the mechanisms underlying this process and the role of chemoattractants and other related tumour microenvironment components is widely overlooked in classic in vitro models. Here, a microfluidic chip composed of two matrix compartments with distinct characteristics is developed to model 3D chemotactic tumour stroma invasion with human breast cancer cells and human cancer-associated fibroblasts. The results showed that an epidermal growth factor transient gradient induced cancer cell invasion, increasing migration speed and persistence. Furthermore, this new setup allowed analysing several features at tissue and cellular level associated with the enhancement of cell invasive behaviour. Overall, the researchers propose a novel platform that recapitulates 3D tumour-stroma interactions and opens the door to better understand the tissue and cellular mechanisms that drive cell invasion in real-time.
Breast cancer cell invasion into a three dimensional tumor-stroma microenvironment
Mehdi Nikkhah
Added on: 10-13-2021
Hydrogel-based 3D breast cancer model
2016
Auburn University, Auburn, USA
To recapitulate the native tumor microenvironment, in this study a new poly-ethylene glycol-fibrinogen hydrogel is used to do 3D culture of three different human breast cancer cell lines. This new model improves cell viability, proliferation and 3D morphology and induces spatial heterogeneity within the hydrogels. Overall, this model shows the potential to be used in drug-testing applications.
PEG-fibrinogen hydrogels for three-dimensional breast cancer cell culture
Elizabeth A Lipke
Added on: 07-18-2021
Microfluidic chip system to model breast cancer in 3D environment
2016
Purdue University, West Lafayette, USA(1)
University of Illinois at Urbana−Champaign, Urbana, USA(2)
University of Illinois at Urbana−Champaign, Urbana, USA(2)
A collagen-based 3D model was coupled to a microfluidic system on a chip that allows independent modulation of matrix stiffness and interstitial fluid flow. This model offers a better adaptation of human breast cancer cells based on immunofluorescence analysis. The tuning of the matrix characteristics will allow to investigate the role of extracellular tumor microenvironments.
Modulation of matrix softness and interstitial flow for 3D cell culture using a cell-microenvironment-on-a-chip system
Bumsoo Han(1), Hyunjoon Kong(2)
Added on: 07-15-2021
New multicellular 3D model for metastasis of breast cancer
2016
Weill Cornell Medical College, New York, USA
New model was developed based on hydrogel-encapsulated human breast cancer cells with a central microchannel populated with human aortic smooth muscle cells and human umbilical vein endothelial cells. In this model, the tumor cells induce aberrant vascular cell organization and matrix remodelling to, finally, migrate to the newly formed vessel. This model shows great potential to study metastasis-related mechanisms and drug target discovery.
A novel three-dimensional platform to investigate neoangiogenesis, transendothelial migration, and metastasis of MDAMB-231 breast cancer cells
Jason A Spector
Added on: 07-15-2021
Signalling pathways involved in metastasis
2016
University of Vienna, Vienna, Austria
Overexpression of aryl hydrocarbon receptor and cytochrome P450 1A1 is linked to the metastatic outgrowth of different cancers. However, the mechanisms underlying this causal correlation still remain elusive. Here, a 3D model based on a lymph endothelial cell monolayer and human breast cancer cell spheroid co-culture was developed to use modulatory strategies and elucidate the molecular basis of aryl hydrocarbon receptor and cytochrome P450 1A1-induced metastatic behaviour. The results showed that aryl hydrocarbon receptor-induced cytochrome P450 1A1 expression and 12(S)-HETE secretion by tumour spheroids, which induced retraction of lymph endothelial cell junctions and transmigration of tumour cells. This could be directly modulated by regulating the aryl hydrocarbon receptor. Furthermore, NF-kB and aryl hydrocarbon receptors were found to be negatively cross-regulated and the inhibition of either pathway was promoting the induction of the downstream targets of the other. Finally, these mechanisms could be inhibited by guanfacine and vinpocetine, leading to an inhibition of lymph endothelial cell monolayer breaching. Overall, the researchers propose a new model used to investigate metastatic mechanisms and elucidate new signalling pathways that can be targeted by currently available drugs.
AHR/CYP1A1 interplay triggers lymphatic barrier breaching in breast cancer spheroids by inducing 12(S)-HETE synthesis
Walter Jäger
Added on: 10-12-2021
3D multicellular model of tumor microenvironment
2016
University of Freiburg, Freiburg, Germany
In recent years, 3D models are becoming increasingly important in drug screening experiments due to their capacity of reproducing key physiological aspects impossible to reproduce in 2D cultures and the possibilities to avoid the complexity of working with animal models. Here, a 3D multicellular spheroid model was built using human lung epithelial cancer cells, human pulmonary vascular cells and human marrow-derived mesenchymal stem cells to reproduce epithelial tumor microenvironment. The results showed that it was possible to observe key characteristics of the in vivo disease that other spheroid cultures fail to reproduce. Moreover, despite having elevated levels of reactive oxygen species and expression of genes associated with drug resistance, cells within the model were more sensitive to paclitaxel and gemcitabine than 2D tri-cultures. Overall, the researchers propose a new 3D spheroid model that contains different cell types and is able to replicate key aspects of cancer pathology, making it a potential tool to perform drug screening and mechanistic studies.
Recapitulating epithelial tumor microenvironment in vitro using three dimensional tri-culture of human epithelial, endothelial, and mesenchymal cells
V Prasad Shastri
Added on: 11-28-2021
CHEK2 regulates paracrine signaling of cancer-promoting factors in fibroblasts
2016
King Saud University, Riyadh, Saudi Arabia
Activated fibroblasts have an important role in tumorigenesis and metastasis in breast cancer. However, the molecular mechanisms of their pro-carcinogenic behaviour are not well understood. Here, patient samples and human breast cancer cells were used to investigate the mechanisms of fibroblast activation and the potential of CHEK2 as an anti-tumor suppressor. The results showed that CHEK2 is down-regulated in cancer-associated fibroblasts. Additionally, knockdown of CHEK2 induced the secretion of SDF-1 and IL-6 and transdifferentiation to myofibroblasts, which promoted proliferation of epithelial cells and increased metastatic capabilities of breast cancer cells through SDF-1/IL-6 paracrine signalling. Finally, the cancer-promoting behaviour of cancer activated fibroblasts could be reverted through forced overexpression of CHEK2. Overall the researchers demonstrate the non-cell-autonomous tumor suppression activity of CHEK2 and elucidate its important role in the regulatory interaction between breast tumors and their stromal fibroblasts.
CHEK2 represses breast stromal fibroblasts and their paracrine tumor-promoting effects through suppressing SDF-1 and IL-6
Abdelilah Aboussekhra
Added on: 10-31-2021
Co-stimulation of cancer vaccines with peptides improves efficiency
2016
Copenhagen University Hospital, Copenhagen, Denmark
Programmed death 1 (PD-1) is expressed on the surface of T cells and its ligands play a central role in maintaining peripheral tolerance and preventing autoimmunity. Cancer cells can exploit this system to create a suppressing microenvironment, thus protecting themselves from immune-mediated killing. Indeed, PD-L1 expression has been found to be high in multiple cancers. In the present study, the researchers used peripheral blood from patients with malignant melanoma who had been treated with dendritic cell (DC)-based vaccine. The cells were used to co-stimulate the vaccine with PD-L1-derived epitopes. Co-stimulation boosted the immune response elicited by the DC vaccine. A significant increase in the number of vaccine-reacting T cells was observed in vitro. In conclusion, activation of PD-L1-specific T cells may directly modulate the immunogenicity of DC vaccines and may be an attractive option to improve the efficiency of immunotherapeutic agents.
PD-L1 peptide co-stimulation increases immunogenicity of a dendritic cell-based cancer vaccine
Mads Hald Andersen
Added on: 07-28-2021
Development of a vascularized tumor-on-chip model
2016
UC Irvine, Irvine, USA
The development of a tumor-on-chip 3D model to recapitulate solid tumor vascularization using human tumor and stromal cells growing in 3D extracellular matrices is presented. This model is able to support breast and colorectal cancer cells growth through living microvessels. Tumors growing in this platform show metabolic heterogeneity, with a preference for aerobic glycolysis. Finally, it is shown that with the use of different agents, it is possible to describe different mechanisms of vascular-targeting drugs, confirming that this can be an interesting model to study vascularized solid tumors and drug testing.
3D microtumors in vitro supported by perfused vascular networks
Christopher C W Hughes
Added on: 07-18-2021
Identification of genes that are important for the development of cancer by means of high-content imaging
2016
University of Queensland, Brisbane, Australia
There is consistent evidence that epithelial-to-mesenchymal transition is a key phenomenon in the development and progression of cancer. Also, it has been elucidated that it has a crucial role in metastasis and drug resistance in some carcinomas. Thus, there is a need to understand the mechanisms underlying this process. Here, the researchers performed high-content imaging to measure cytoplasmatic vimentin of human breast cancer cells transduced with a library of 17000 human open reading frames. Afterwards, the selected hits were validated in a non-tumorigenic breast epithelial cell line. The validated hits induced cell invasion and mesenchymal marker expression, reducing E-cadherin expression. Finally, newly identified genes were shown to be correlated with the expression of epithelial-to-mesenchymal transition marker genes in datasets from breast cancer patients. In summary, several new genes that contribute to epithelial-to-mesenchymal transition are identified and functionally validated in this study, which may lead to their further development as potential targets for anti-cancer therapy.
Genome-wide gain-of-function screen for genes that induce epithelial-to-mesenchymal transition in breast cancer
Thomas J Gonda, Dubravka Škalamera
Added on: 10-27-2021
Let-7 miRNAs disrupt triple-negative breast cancer stem cells activity
2016
The First Affiliated Hospital of Zhengzhou University, Henan, China
Let-7 miRNAs family has been shown to be able to disrupt the normal functioning of cancer stem cells. However, their therapeutic potential in cancers with a bad prognosis like triple-negative breast cancer remains unknown. Here, different in vitro models using human breast cancer cell lines were used to investigate the inhibitory effect of let-7 miRNAs on self-renewal abilities of triple-negative breast cancer stem cells. The results showed that let-7 could reduce the number of mammospheres and had synergistic effects with radiation on hindering stem cell renewal. Moreover, the signalling pathway by which let-7 acts was identified. Consequently, the re-activation of the let-7 inhibited pathway through recombinant protein signalling abolished the effects of let-7. Overall, the researchers deciphered the signalling pathway involved in the anti-tumor activity of let-7 miRNAs family and suggest new therapeutic targets to reduce cancer stem cell activity in triple-negative breast cancer treatment.
Let‑7 miRNAs sensitize breast cancer stem cells to radiation‑induced repression through inhibition of the cyclin D1/Akt1/Wnt1 signaling pathway
Jianbo Gao
Added on: 10-31-2021
Possible combination of a drug and immunotherapy tested in ex vivo immune cells
2016
IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy(1)
University of Genoa, Genoa, Italy(2)
University of Genoa, Genoa, Italy(2)
Melanoma has an incidence that is increasing at a rate faster than any other solid malignancy. Approximately 50% of cutaneous melanomas harbour a somatic mutation in the gene encoding BRAF, a serine/threonine protein kinase. Therapies based on mutated BRAF- inhibitors have been developed for melanoma treatment. Combined with immunotherapy, they could represent a promising strategy for the cure of melanoma. In the present study, the researchers aimed at clarifying the actual efficacy of combination treatments involving inhibitors and NK cell-based immunotherapy, as well as the occurrence of possible interference with NK cell function. NK cells were isolated from donors and cultured in vitro with different concentrations of BRAF inhibitor to show that there was no effect on the functional properties of NK cells. The data suggest that oncogene-targeting drugs are compatible with NK-based adoptive therapy.
Cytokines can counteract the inhibitory effect of MEK-i on NK-cell function
Lorenzo Moretta(1), Gabriella Pietra(2)
Added on: 09-18-2021
Relation between obesity, inflammation and severity of prostate cancer tested in patients' tissue
2016
Thomas Jefferson University, Philadelphia, USA
Obesity is a potentially modifiable risk factor for disease progression and poor outcomes for numerous diseases, including prostate cancer (PCa). One possible link in the relationship between obesity and PCa progression is inflammation. Obesity produces a state of systemic chronic low-grade inflammation that can contribute to a number of chronic diseases, including advanced PCa. In the present study, the researchers aimed at examining prostatic inflammation via tumor-infiltrating lymphocytes and macrophages characterized by obesity and cancer severity.
Prostate tissue from 99 participants (63 non-obese and 36 obese) were analyzed for type and count of lymphocytes and macrophages and the pathology data were linked to clinical and demographic variables. The results showed that the number of lymphocytes and macrophages in the tumor microenvironment did not differ by obesity status. However, these inflammation markers were associated with poor prostate cancer outcomes. Further examination of underlying mechanisms that influence obesity-related effects on prostate cancer outcomes is still needed to guide immunotherapy protocols and weight management as they apply to diverse patient populations and phenotypes.
The relationship between obesity, prostate tumor infiltrating lymphocytes and macrophages, and biochemical failure
Charnita Zeigler-Johnson
Added on: 09-17-2021
TBX3 promotes cancer progression
2016
Western University, London, Canada
The transcriptional regulator TBX3 has been described as a promoter of malignancy of tumour cells. More specifically, it was observed that it may promote cell survival and epithelial-to-mesenchymal transition. Here, TBX3 expression is modulated in three different cell lines of human breast cancer, representing distinct stages of cancer progression, to investigate the role of this factor in cancer-related features. The results showed that TBX3 is naturally more abundant in invasive breast cancer cells than in other cancer cell types. The overexpression of different isoforms of TBX3 resulted in the induction of cancerous behaviour in cells cultured in Matrigel in a 3D setup. Accordingly, when TBX3 was knocked down, there was a decrease in cancer-associated properties. Moreover, the transcriptomic analysis of cells with upregulated TBX3 corroborated the presence of alterations in cell survival, epithelial-to-mesenchymal transition, invasiveness and others. Overall, the researchers confirm that TBX3 is involved in several cell processes occurring during cancer progression and that it may be a key regulator of several cancer hallmarks.
The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer
Alan B Tuck
Added on: 10-20-2021
Ex vivo stimulation of immune cells from patients with cancer antigen
2016
Justus-Liebig-University, Giessen, Germany
Anaplastic lymphoma kinase (ALK) in patients with ALK-positive anaplastic large cell lymphoma (ALCL) is an attractive target for immune therapy. In this study, the researchers aimed to evaluate the response of ALK-specific T cells in ALCL patients. The researchers used autologous dendritic cells (DCs) transfected with RNA (IVT-RNA) encoding ALK to be used as antigen-presenting cells for T cell stimulation in vitro. ALK-specific T cell responses were detected in three of five ALK-positive ALCL patients tested. Further analysis of a larger unselected cohort of patients is planned to define whether the strength of the T cell response correlates with the ALK-antibody titre and clinical characteristics.
Analysis of nucleophosmin–anaplastic lymphoma kinase (NPM-ALK)- reactive CD81 T cell responses in children with NPM-ALK1 anaplastic large cell lymphoma
W. Woessmann
Added on: 07-29-2021
Extracellular matrix regulates epigenetic changes in breast cancer
2016
China Medical University, Shenyang, China(1)
Washington State University Spokane, Spokane, USA(2)
Washington State University Spokane, Spokane, USA(2)
Different subtypes of breast cancer have different epigenetic signatures that can regulate gene expression and produce specific transcriptomic profiles. This differential epigenetic regulation can depend on the tumor microenvironment. In human patients, Claudin-low breast cancer is associated with triple-negative invasive ductal carcinomas. Here, a laminin rich extracellular matrix organotypic culture is used with human breast cancer cells to model Claudin-low breast cancer and explore the extracellular matrix-dependent epigenetic regulation of homeobox genes in cancer progression. The results showed that epigenetic changes induced the expression of certain homeobox genes and were dependent on interactions with the extracellular matrix through the binding of bromodomain-containing 4 to the HOXA9 promoter. In this study, the researchers demonstrate the importance of extracellular matrix-regulated epigenetic modulation of gene expression in a 3D human model of a subtype of breast cancer that can sustain the further development of new targets and therapeutical strategies.
Induction of HOXA9 expression in three-dimensional organotypic culture of the Claudin-low breast cancer cells
Miao Li(1), Bin Shan(2)
Added on: 10-25-2021
Optimal conditions to expand ex vivo patients T cells
2016
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Adoptive T cell therapy (ACT) represents a highly promising strategy to treat cancer. While this approach has been mostly based on the use of terminally differentiated effector T cells, recent studies indicate that the use of less differentiated T cells with extensive replicative capacity has greater engraftment and antitumor effect, in particular, the recently described memory stem T cells (TSCM). Methods to generate memory stem T cells ex vivo rely on peptides and cytokines during the culture period yet too strong stimulation may induce differentiation of memory stem T cells to effector memory T cells. In the present study, the researchers purified naïve T cells from healthy donors which were then cultured ex vivo in the presence of different combinations of peptides and cytokines during different times. T cells phenotype was then assessed by multiparametric flow cytometry. The study shows which are the optimal conditions to increase the frequencies and expansion of memory stem T cells.
A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy
J. Briones
Added on: 09-15-2021
Plant extract inhibits breast cancer stem cell proliferation
2016
Vietnam National University, Ho Chi Minh City, Vietnam
Methanol and ethanol-based extracts of "Taraxacum officinale" are applied to a 2D and a 3D model of isolated human breast cancer stem cells. Methanol based extracts could be used as potential anti-cancer drugs, as they are more efficient in inhibiting the proliferation of breast cancer stem cells and induce expression of apoptosis-associated and reactive oxygen species-associated factors.
Taraxacum officinale dandelion extracts efficiently inhibited the breast cancer stem cell proliferation
Phuc Van Pham
Added on: 07-11-2021
Quantitative and reproducible method to evaluate outcomes in cancer
2016
Yale University, New Haven, USA
With the advent of effective immunotherapies for cancer, there has been renewed interest in the tumor immune infiltrate. A number of studies have shown the prognostic value of the presence of tumor-infiltrating lymphocytes (TILs) in a range of cancer types. Alas, the issue of assessment of TILs is problematic and has been addressed by an international consortium of pathologists. In the present study, the researchers have used a previously validated immunocytochemistry and image analysis approach to measure TILs in collected biopsies from three different regions of resected breast tumors. The study describes the distribution of different TIL phenotypic markers, both within separate regions of a tumor and within a given tissue section, and then apply statistical analysis to determine the degree of variance for each marker across the tumor. The study show application of an objective and reproducible assay to quantify the distribution of TIL expression in breast tumors. Future studies with larger patient populations with outcome data are needed to validate this observation.
Quantitative assessment of the spatial heterogeneity of tumor-infiltrating lymphocytes in breast cancer
David L. Rimm
Added on: 09-15-2021
Tissue clearing of cancer spheroids for high-throughput analysis
2016
The University of British Columbia, Vancouver, Canada
In this study, the researchers develop a microfluidic system to allow the tissue clearing of spheroids of human breast cancer cells directly on-chip systems. This allows for on-chip high-throughput analysis and opens new possibilities for monitoring small 3D cultures during cell-based assays for high-content drug screening.
On-chip clearing of arrays of 3-D cell cultures and micro-tissues
K C Cheung
Added on: 07-12-2021
Angiogenesis control with hydrogels in cancer context
2016
Bulgarian Academy of Sciences, Sofia, Bulgaria
Gelatin-based hydrogels are used to test the response of human umbilical vein endothelial cells and human invasive breast cancer cells to different matrix properties and electrical fields. The results showed that gelatin materials can suppress the attachment of cancerous cells and suppress their angiogenic potential compared to human umbilical vein endothelial cells. Thus, this model can be a potential tool for tissue regeneration or tumor growth restriction.
Angiogenic potential of endothelial and tumor cells seeded on gelatin-based hydrogels in response to electrical stimulations
Rumiana Tzoneva
Added on: 07-30-2021
Cancer therapies combination assisted by mathematical modeling
2016
Aix Marseille University, Marseille, France(1)
Assistance Publique-Hopitaux Marseille, Marseille, France(2)
Assistance Publique-Hopitaux Marseille, Marseille, France(2)
Combining radiotherapy with immunotherapy may offer a considerable therapeutic impact. In this study, the researchers propose a set of mathematical equations that describe the pharmacodynamics of radiotherapy in combination with two paradigmatic immunotherapies used. The modelling offers an explanation for the reported biphasic relationship between the size of a tumor and its immunogenicity and how synchronizing immunotherapy and radiotherapy can produce synergies. The ability of the model was validated retrospectively by checking data from experimental studies. Such a model could further facilitate decision making about optimal scheduling of immunotherapy with radiotherapy.
Mathematical modeling of cancer immunotherapy and its synergy with radiotherapy
Dominique Barbolosi(1), Xavier Muracciole(2)
Added on: 07-26-2021
Combination of immunotherapy approaches tested on cancer cell lines
2016
Cancer Center Amsterdam, Amsterdam, Netherlands
Using the ability of Natural Killer (NK) cells to kill liquid tumors as a therapeutic strategy is deep in its development but is in its early phases for solid tumors. Epidermal Growth Factor Receptor (EGFR) activates important pathways which control cell proliferation, survival and motility. Accordingly, dysregulation of the EGFR signalling cascade can support tumor growth and EGFR expression levels are elevated in many cancers. In the present study, the researchers aimed at examining the efficacy of anti-EGFP antibody treatment in combination with other treatments. Immune cells, Natural Killers, were prepared from peripheral blood and activated and used in combination with anti-EGFR antibodies to test their cytotoxic activity against cancer cells in vitro. The studies demonstrated an enhancement of cytotoxicity of NK cells when used in combination with anti-EGFR antibody.
Combination of NK cells and cetuximab to enhance anti-tumor responses in RAS mutant metastatic colorectal cancer
Hans J. van der Vliet
Added on: 09-17-2021
Generation of novel immunotherapy and testing of blood cancer patients' cells
2016
Peking University Shenzhen Graduate School, Shenzhen, China(1)
South University of Science and Technology of China, Shenzhen, China(2)
South University of Science and Technology of China, Shenzhen, China(2)
CD38, as a cell surface antigen, is highly expressed in several hematologic malignancies and has been proven to be a good target for immunotherapy of the disease. In this study, the researchers aimed at targeting CD38 as an anti-cancer target by generating a series of nanobodies against CD38 with high affinities. To do this, they generated crystal structures of the complexes of CD38 and identified target epitopes. Chromobodies were generated to check CD38 expression in patients cells and results confirmed that CD38 was highly expressed in malignant MM cells compared with normal white blood cells. Further, the researchers generated an immunotoxin from the nanobodies which showed highly selective cytotoxicity against patient-derived MM cells as well as human cell lines. These results set the stage for the development of clinical therapeutics as well as diagnostic screening for myeloma.
Immuno-targeting the multifunctional CD38 using nanobody
Yong Juan Zhao(1), Hon Cheung Lee(1), Hongmin Zhang(2)
Added on: 07-28-2021
Humanised matrix-free 3D platform to investigate cancer mechanisms
2016
University of Leeds, Leeds, United Kingdom
In recent years, 3D cultures are emerging as a reliable tool to model diseases in vitro due to their close mimicking of in vivo tissue characteristics. Here, three different 3D setups are used to culture different subtypes of human breast cancer cells alone or co-cultured with human mammary fibroblasts to develop matrix-free humanized models of breast cancer. The results showed that a 3D collagen I system supported a wide range of breast cancer cell subtypes and a modification of the Fibrolife system made possible matrix-free cell culture. With this last system, breast cancer cells had a progressive detachment from the surface and formed spheroids with proliferating cells that kept a stable morphology. Furthermore, the co-culture with fibroblasts in low-attachment vessels resulted in efficient co-culture of both cell types with a similar organisation to that in vivo. Overall, the researchers develop a new humanised 3D matrix-free platform to investigate the interplay between fibroblasts and human cancer cells with the potential of facilitating the discovery of new disease mechanisms.
An evaluation of matrix-containing and humanised matrix-free 3-dimensional cell culture systems for studying breast cancer
Valerie Speirs
Added on: 11-02-2021
Imaging-coupled 3D model to study tumor microenvironments
2016
University of Michigan Medical School, Ann Arbor, USA
The study presents a combination of an imaging device with a 3D model of quiescent breast cancer cells with bone marrow cells to perform drug testing. Through label-free methods, the researchers find that bone marrow stromal cells are capable of controlling the metabolism of co-cultured breast cancer cells. Therefore, the modulation of specific metabolic pathways can eliminate those quiescent breast cancer cells. Thus, confirming that this imaging-coupled spheroid model can be used to study tumor microenvironments.
Imaging sensitivity of quiescent cancer cells to metabolic perturbations in bone marrow spheroids
Gary D Luker
Added on: 07-14-2021
Mathematical model for reactive oxygen species-induced cell death mechanisms
2016
University of Waterloo, Waterloo, Canada
A mathematical model is used to understand and decipher the mechanisms of ascorbic acid-induced cytotoxicity on cancer cells. This model determines that reactive oxygen species-induced cell death relies on membrane properties. This is confirmed with experimental data from in vitro assays with human breast cancer cells. These findings provide key insights in the mechanisms of ascorbic acid-induced cancer cell death and confirm this model as a potential tool to understand the mechanisms of selective drugs.
Drug-induced reactive oxygen species (ROS) rely on cell membrane properties to exert anticancer effects
Mohammad Kohandel, Hamid R Molavian
Added on: 07-21-2021
Obscurins disrupt tumor and metastatic behaviour in breast epithelial cells
2016
University of Maryland School of Medicine, Baltimore, USA
Obscurins were first described as cytoskeletal proteins with structural and regulatory roles, but recent studies have described this family of proteins to be involved in tumour and metastasis suppressing functions in normal breast epithelial cells. Furthermore, the loss of these proteins in the same tissue is correlated to physiological changes linked to tumour and metastatic behaviour. Here, giant obscurins are knocked-down in a human non-tumourigenic breast epithelial cell line to perform mechanistic studies. The results elucidated that the loss of giant obscurins induced the activation of PI3K and subsequent activation of AKT cascade. The inhibition of PI3K signalling pathway in the same conditions reversed the effect of the loss of giant obsucrins, inhibiting the transition towards cancerous cell behaviour. Finally, it was revealed that obsucrins are directly related to PI3K/p85 through the formation of complexes. Overall, the researchers use diverse methods coupled with gene expression modulation techniques to elucidate the role of giant obscurins in the prevention of tumour progression and propose a signalling pathway as the mechanistic explanation for it, pointing towards a new potential therapeutical target for metastasis prevention.
Giant obscurins regulate the PI3K cascade in breast epithelial cells via direct binding to the PI3K/p85 regulatory subunit
Aikaterini Kontrogianni-Konstantopoulos
Added on: 10-13-2021
Platform development to study bone metastasis
2016
The George Washington University, Washington DC, USA
Bone metastasis is one of the most common complications of late-stage breast cancer. Thus, there is a need to develop in vitro models that integrate breast cancer cells with bone matrix components to improve the understanding of the mechanisms underlying breast cancer bone invasion. Here, in vitro 3D printed hydrogel-based bone matrices are used to co-culture directly, in 2D or 3D formats, or indirectly human breast cancer cells and human fetal osteoblasts. The results showed that indirect co-culture inhibited osteoblast proliferation while increasing breast cancer cell growth and IL-8 secretion in both cell types. Moreover, the direct 3D culture setup allowed the formation of multi-cellular spheroids. In this study, the researchers develop different 3D printed bone matrices setups that can be used to investigate the mechanisms underlying bone metastasis in vitro through different approaches.
A 3D printed nano bone matrix for characterization of breast cancer cell and osteoblast interactions
Lijie Grace Zhang
Added on: 10-04-2021
New human cell line as a tool for therapy development in renal cancer
2016
University of Foggia, Foggia, Italy
Renal cell carcinoma (RCC) is the most common kidney cancer. In this study, the researchers established one new cell line from one RCC patient and characterized it by genomics, proteomics and immunological analysis. The novel established immunogenic cell line will be suitable for immune stimulation. The identification of novel tumour-associated antigens will allow the evaluation of the immune response in vitro and, subsequently, in vivo paving the way for new immunotherapeutic strategies in the RCC setting.
Establishment and characterization of a highly immunogenic human renal carcinoma cell line
Elena Ranieri
Added on: 07-27-2021
Screening platform for assessment of NK cell cytotoxicity
2016
Karolinska Institutet, Tumor and Cell Biology, Stockholm, Sweden(1)
KTH – Royal Institute of Technology, Solna, Sweden(2)
KTH – Royal Institute of Technology, Solna, Sweden(2)
Cytotoxic effector lymphocytes, such as natural killer (NK) cells and T cells, are important for immune defence against cancer and viral infections, the traits that have made these cells valuable in adoptive cell therapy. This screening platform can be used for assessment of the cytotoxic potential of individual natural killer (NK) cells within larger populations. Human primary NK cells were distributed across a silicon–glass microchip containing a high number of individual microwells loaded with target cells. Through fluorescence screening and automated image analysis, the numbers of NK and live or dead target cells in each well could be assessed at different time points after initial mixing. Cytotoxicity was also studied by time-lapse live-cell imaging in microwells quantifying the killing potential of individual NK cells. Moreover, the screening approach was adapted to increase the chance to find and evaluate serial killing NK cells. This approach could find use in clinical applications, e.g., in the selection of donors for stem cell transplantation or generation of highly specific and cytotoxic cells for adoptive immunotherapy.
Microchip screening platform for single cell assessment of NK cell cytotoxicity
Björn Önfelt(1, 2)
Added on: 05-27-2020
Spheroid breast cancer model to select individual treatments
Company 2016
SpheroTec GmbH, Martinsried, Germany
Treatment for HER2+ breast cancer patients has greatly improved prognosis in recent years. However, there is a lack of specific treatment for HER2- breast tumors. Thus, there is a need to develop tools that allow for a better patient-specific drug screening that can increase treatment efficacy. Here, an in vitro tissue human breast tumor spheroid model was used to test different compounds and compared to homogenous cell tumors generated with HER2- human breast cancer lines. The results showed cell line-based spheroids had higher metabolic activity and cell viability and this was correlated to a lower number of cells in the tumor model, contrary to heterogeneous spheroids. Moreover, except for taxanes, most of the compounds had differential responses between tissue models and breast cancer cell lines spheroids. Finally, tissue-based spheroids presented high variability in drug responses and corresponded to current guidelines recommendations. Overall, the researchers present a model that can potentially be used as a diagnostic tool to select efficient treatment strategies in individual patients.
Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids
Barbara Mayer
Kathrin Halfter et al. Journal of Translational Medicine 2016 [749]
EURL ECVAM [750]
SpheroTec GmbH [751]
Added on: 10-05-2021
3D printed scaffolds to optimise breast cancer stem cell culture
2016
University of Girona, Girona, Spain
With the use of a RepRap BCN3D+ 3D printer, the researchers printed different scaffolds using poly(ε-caprolactone) to optimise human breast cancer stem cell culture. Compared to 2D monolayer culture, with the optimal printing configuration, these scaffolds allowed for a 3D culture that induced a higher mammosphere forming index, showing enrichment of human breast cancer stem cells in the cultures. This new setup could be a good method to obtain enriched breast cancer stem cell cultures.
Breast cancer stem cell culture and enrichment using poly(ε-caprolactone) scaffolds
Joaquim Ciurana, Teresa Puig
Added on: 07-27-2021
Characterization of dysfunctional regulatory cells in malignant gliomas
2016
Yale School of Medicine, New Haven, USA
Developing a clear immunological understanding of how immunotherapies work — particularly with respect to the phenotype and function of the cells they target — should enable further improvements of these therapies in the clinic. Immunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. In the present study, the researchers examined functional and molecular features of regulatory T cells positive for PD-1 isolated from patients with glioblastoma multiforme and healthy donors, combining functional assays, RNA sequencing, and cytometry. Overall, patients were shown to display enrichment in dysfunctional regulatory T cells which is in contrast with the current view. The study suggests a need for a more precise single-cell characterization of regulatory T cells to improve immunotherapy design.
PD-1 marks dysfunctional regulatory T cells in malignant gliomas
David A. Hafler
Added on: 09-14-2021
Neuroblastoma patients response to immunotherapy predicted by genetic profiling
2016
Memorial Sloan Kettering Cancer Center, New York, USA
Half of the patients with neuroblastoma (NB) have a high-risk disease at diagnosis with poor long-term survival. Monoclonal antibody (mAb) therapies directed at disialoganglioside GD2 mediate the action of Natural Killer cells (NK cells) and have been a major advancement in the treatment of NB. NK cells activity rely on the presence and interaction of certain cell surface receptors and ligands. In the present study, the researchers aimed at understanding if a specific combination of one cell surface receptor and ligand could help to predict the outcome of patients treated with monoclonal antibodies. A cohort of patients was genetically profiled for the presence of receptor and ligand and was correlated with patients outcomes following treatment. The results showed the best outcome when the patient has weak interacting receptors and ligands, hence potentially helping the prediction of prognosis.
KIR3DL1 allelic polymorphism and HLA-B epitopes modulate response to anti-GD2 monoclonal antibody in patients with neuroblastoma
Katharine C. Hsu
Added on: 09-17-2021
Virtual screening of HER2-targeting drugs
2016
Alagappa University, Karaikudi, India
Using delphinidin as a query parent, this study is based on searching for homologous compounds that have safer pharmacological profiles for HER2 targeting in human breast cancer. After a screening of PubChem database and further validation procedures, a compound was identified with a higher affinity than delphinidin and a better ADMET profile. This study can serve as a starting point for the "in vitro" assessment of this identified HER2-targeting drug.
Virtual screening approaches in identification of bioactive compounds akin to delphinidin as potential HER2 inhibitors for the treatment of breast cancer
Sanjeev Kumar Singh
Added on: 07-30-2021
3D hydrogel-based model of metastasis
2016
Arizona State University, Tempe, USA
A gelatin methacrylate hydrogel is used combined with photolithography to produce a tunable 3D model of human breast cancer metastasis. Using different cell lines, including human breast cancer and non-tumorigenic mammary epithelial cells, it is confirmed that this 3D platform can enhance different cell-specific behaviours, like invasive processes or cluster formation, and analyze them. Therefore, this model represents a promising development to use 3D tumor models to study human breast cancer metastasis.
A three dimensional micropatterned tumor model for breast cancer cell migration studies
Mehdi Nikkhah
Added on: 07-23-2021
3D model to investigate metabolic response of lung cancer cells
Company 2016
Harvard University, Cambridge, USA(1)
Vertex Pharmaceuticals Incorporated, Boston, USA(2)
Vertex Pharmaceuticals Incorporated, Boston, USA(2)
In previous studies, a paper-based 3D culture system was developed, which can generate oxygen and nutrient gradient along the different layers. Here, it was used to investigate metabolic responses of human lung adenocarcinoma cells to ionizing radiation by calculating the availability of nutrients and oxygen in each layer, depending on the distance from the source, correlated to the metabolic activity of the cells. The results showed that there was a positive correlation between distance from the source and increased markers of hypoxia and metabolic stress and reduced sensitivity to ionizing radiation, replicating features of in vivo cancer cell behaviour in solid tumors. Finally, three different isogenic variants were identified, corresponding to the different types of metastatic behaviour in vivo. Overall, the researchers demonstrate that this 3D paper-based model can reproduce some characteristics of radiosensitivity of cancer cells to perform radiation response studies without the influence of cell migration and proliferation and controlling metabolic parameters at different time-points.
Metabolic response of lung cancer cells to radiation in a paper-based 3D cell culture system
George M Whitesides(1), Brenda K Eustace(2)
Added on: 11-28-2021
3D multicellular tumor model with defined tumor microenvironment
2016
Biotec TU Dresden, Dresden, Germany
There is growing evidence that the interactions between tumor microenvironment and tumor cells play a key role in cancer progression. Some of the extracellular matrix proteins present in the extracellular space are implicated in cancer cell survival and invasive behaviour and tumor cells often drive extracellular matrix remodelling. However, there is a lack of experimental platforms that can reliably replicate this interplay in an in vitro 3D context. Here, a new 3D model with a motif-defined hydrogel-based extracellular matrix is developed and combined with the culture of human breast or prostate cancer cells alone or in combination with endothelial and mesenchymal stromal cells. The results showed that the most aggressive human cancer cell line exhibited an invasive morphology with enhanced cell growth and endothelial cell infiltration in hydrogels with collagen I and laminin-111 motifs. In this study, the researchers present a new multicellular 3D model with precisely defined biochemical cues that could be used to further dissect the mechanisms underlying extracellular matrix modulation of cancer progression and potentially help to find new therapeutic strategies that interfere with cancer cell invasion.
3D extracellular matrix interactions modulate tumour cell growth, invasion and angiogenesis in engineered tumour microenvironments
Anna V Taubenberger
Added on: 10-04-2021
Immunoscore method improves prediction of colorectal cancer survival
2016
Pierre and Marie Curie University, Paris, France
Microsatellite instability in colorectal cancer predicts favourable outcomes although the mechanistic link is still unclear. In the present study, the researchers performed a comprehensive analysis of microsatellite-instable patients' tumors using Immunoscore, a scoring system based on the quantification of cytotoxic and memory T cells in the core of the tumor and in the tumor’s invasive margin. The researchers demonstrated the superiority of Immunoscore over microsatellite instability in predicting survival. Thus, the immune infiltration and Immunoscore should better define the prognosis of colorectal cancer patients and identify the ones at risk of tumor recurrence.
Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability
Jerome Galon
Added on: 07-27-2021
Microfluidic 3D model of lung cancer and tumour microenvironment
2016
Dalian Medical University, Dalian, China(1)
The People’s Hospital of Peking University, Beijing, China(2)
The People’s Hospital of Peking University, Beijing, China(2)
The tumour microenvironment is a key element in cancer development comprised of cancer and stromal cells, like cancer-associated fibroblasts, which have a central role in tumour progression. Additionally, another component that has been shown to be implicated in cancer progression is glucose-regulated protein 78. Here, a microfluidic 3D co-culture device is developed with human lung adenocarcinoma cells and fibroblasts to mimic tumour microenvironment and investigate the underlying mechanisms of tumour invasion. The results showed that cancer-associated fibroblasts induced cell migration and glucose-regulated protein 78 expression in lung cancer cells. Further confirmation of glucose-related protein 78 involvement in cell invasion was obtained through knockdown strategies, which blocked cancer cell metastatic behaviour. Overall, the researchers elucidate a major role of glucose-regulated protein 78 in cancer cell migration and propose a new microfluidic 3D device that can be used to investigate the interactions of cancer and stromal cells with the tumour microenvironment.
Cancer-associated fibroblasts promote non-small cell lung cancer cell invasion by upregulation of glucose-regulated protein 78 (GRP78) expression in an integrated bionic microfluidic device
Qi Wang(1), Zhancheng Gao(2)
Added on: 11-26-2021
miRNAs as biomarkers of breast cancer
2016
Georgetown University Medical Center, Washington, USA
In recent years, microRNAs have been described as potential solid biomarkers for breast cancer detection and evaluation. However, there is still high variability among different studies, which leads to difficulties in the interpretation of the data. Other sources than blood have the potential to be used for biomarker detection and solve some of its limitations, like ductal lavage and nipple aspirate fluids. Here, fluid from the ductal lavage of breast cancer patients was used to perform a miRNA transcriptomic analysis. The results identified 17 differentially expressed miRNAs in breast tumors related to several processes of breast cancer development and metastasis. These miRNAs were not limited to this fluid, but could also be detected in samples of other origins. Several signalling pathways involved in breast cancer were elucidated through the analysis of the candidate miRNAs. Additionally, it was described that the miRNA expression profile was specific to different histological types of the tumors. Overall, the researchers demonstrate that the analysis of miRNAs in the ductal fluid can be a potential tool to be used as biomarkers of breast cancer with non-invasive procedures.
MicroRNA analysis of breast ductal fluid in breast cancer patients
Bassem R Haddad
Added on: 10-25-2021
3D platform to perform drug screening for lung cancer
2016
Dalian Medical University, Dalian, China
In vitro cell models are a popular choice to investigate the mechanisms of cancer development and perform drug testing. However, there are still severe limitations to replicating accurately the biological processes that drive non-small-cell lung cancer. Here, a hydrogel-based 3D culture system is used to reproduce an appropriate tumor microenvironment to culture human lung cancer cells and improve drug testing. The results showed good viability of cancer cells that formed aggregates with relevant tissue-like morphology. Moreover, EGF and EGFR were upregulated in 3D cultures, which enabled the researchers to reliably corroborate that EGFR inhibitors could inhibit aggregate growth and induce drug resistance. Overall, the researchers develop a new 3D platform that improves the in vitro modelling of lung cancer and provides a solid tool for drug discovery and testing.
Bioengineering three-dimensional culture model of human lung cancer cells: an improved tool for screening EGFR targeted inhibitors
Xiu-Li Wang, Li-Jun Yu
Added on: 11-02-2021
Mathematical model to improve local radiotherapy site decision
2016
H. Lee Moffitt Cancer Center & Research Institute, Tampa, USA
For many years it has been speculated that localized radiotherapy for cancer metastases can occasionally generate a host immunotherapeutic response known as the abscopal effect. In the present study, the researchers describe a mathematical model that incorporates physiological information about immune cell trafficking through the patient circulatory system. The study shows that immune cell distribution varies significantly between different metastatic sites and depends on the immune system activation site. The presented framework could be used to inform about patient-specific treatment targets in metastatic patients.
The ability to purposefully and reliably induce abscopal effects in metastatic tumors could meet many unmet clinical needs.
Abscopal benefits of localized radiotherapy depend on activated T cell trafficking and distribution between metastatic lesions
Jan Poleszczuk
Added on: 07-26-2021
Method to generate immune killer cells against cancer from patients' blood
2016
Aichi Cancer Center Research Institute, Aichi, Japan(1)
Kyoto University, Kyoto, Japan(2)
Kyoto University, Kyoto, Japan(2)
A subset of T lymphocytes called invariant natural killer (iNKT) recognizes lipid antigens presented on antigen-presenting cells and induces both innate and adaptive immune responses against cancer. Reduced iNKT cell numbers and functions have been observed in many patients with cancer. In the present study, the researchers aimed at establishing a method to increase the population of iNKT. The researchers generated induced pluripotent stem cells (iPSCs) from peripheral blood of healthy donors and reprogrammed them into human iNKT cells. In vitro assays were then used to characterize these iNKT cells and show their cytotoxicity potential against human cancer cell lines. These cells are unlimited and offer potentially effective immunotherapy against cancer.
Cellular adjuvant properties, direct cytotoxicity of re-differentiated Va24 invariant NKT-like cells from human induced pluripotent stem cells
Yasushi Uemura(1), Shin Kaneko(2)
Added on: 07-27-2021
Tumor slice culture for drug validation
2016
Erasmus University Medical Center, Rotterdam, Netherlands
In the present study, a new method for culturing of human breast cancer tumor samples is developed. Several culture parameters are optimized to define specific conditions to grow tumor slices for a minimum of 7 days. Additionally, another method is developed to screen the cytotoxicity of the chemotherapeutic treatment FAC (5-FU, Adriamycin and Cyclophosphamide). The results show that this new platform is able to correctly predict resistant tumors from others, confirming the model's potential to improve personalized breast cancer treatment.
Tumor slice culture system to assess drug response of primary breast cancer
Dik C van Gent
Added on: 07-27-2021
3D simplifed model to investigate metastatic mechanisms
December 2015
Harvard University, Cambridge, USA
Tumor microenvironment is a critical factor in cancer development. Currently, in vitro methods to model cancer rely on monolayer cultures that poorly reproduce the complex environmental context. Although 3D models are rising as an alternative in cancer modelling, there are still severe limitations. Here, a paper-based platform with co-cultures of primary human lung tumor cells and fibroblasts were used to investigate the influence of tumor microenvironment in cancer cells. The results showed that cancer cells migrated towards the layers with fibroblasts and this was exacerbated when directly co-cultured together. This effect was hindered by TGF-beta inhibition, which also reduced epithelial-to-mesenchymal transition. Overall, the researchers develop a simple method to produce relevant 3D structures to study metastatic behaviour of cancer cells alone or in combination with other cell types.
Fibroblasts enhance migration of human lung cancer cells in a paper-based coculture system
George M Whitesides
Added on: 11-27-2021
Development and validation of a microfluidic 3D tumor model
December 2015
Northeastern University, Boston, USA
Here the researchers describe the development of a new microfluidic chip-based platform to study tumor spheroids in a 3D environment. Validation of this model is performed using a breast cancer cell line alone and in co-culture with fibroblasts. This model provides a new tool for performing omics studies and drug screening.
Generation and functional assessment of 3D multicellular spheroids in droplet based microfluidics platform
T Konry
Added on: 07-02-2021
Immunosensor for breast cancer diagnostics
December 2015
IK4-Tekniker, Eibar, Spain
The study describes the development of an immunosensor for ErbB2 breast cancer biomarker that allows for enhanced detection compared to current methods. When tested in human serum and in several human breast cancer cell lines, the sensor showed to have very effective detection rates. Therefore, this highly sensitive immunosensor is a feasible tool for ErbB2 detection and breast cancer diagnosis.
Surface plasmon resonance immunosensor for ErbB2 breast cancer biomarker determination in human serum and raw cancer cell lysates
Josu Martinez-Perdiguero
Added on: 07-30-2021
Immunosensor for breast cancer monitoring
December 2015
IK4-Tekniker, Eibar, Spain(1)
Universidad Complutense de Madrid, Madrid, Spain(2)
Universidad Complutense de Madrid, Madrid, Spain(2)
The study describes the development of a magnetoimmunosensor that allows monitoring of breast cancer through progesterone receptor detection and estrogen receptor alpha. The detection limits of this sensor were very low and when tested with two different human breast cancer cell lines, it was capable of discriminating between them. Its performance and simplicity can outperform ELISA's as the standard technique for diagnosis and monitoring of metastatic breast cancer.
Electrochemical magnetoimmunosensor for progesterone receptor determination. Application to the simultaneous detection of estrogen and progesterone breast-cancer related receptors in raw cell lysates
J Martinez-Perdiguero(1), S Campuzano(2)
Added on: 08-01-2021
Characterization of three cell lines for breast cancer modeling
November 2015
Federal Institute for Risk Assesment, Berlin, Germany
In this study, the authors characterize three human breast cancer cell lines to investigate if they are suitable for breast cancer modelling. They use transcriptomics, cell viability assays, apoptosis assays and morphological characterization in spheroid cultures to determine the potential of these lines.
Morphological and molecular characterization of the human breast epithelial cell line M13SV1 and its tumorigenic derivatives M13SV1-R2-2 and M13SV1-R2-N1
Thorsten Buhrke
Added on: 07-03-2021
Human stem cell model of neuromuscular junction affected by the autoimmune disorder myasthenia gravis
November 2015
Sloan-Kettering Institute for Cancer Research, New York, USA
Myasthenia gravis is an autoimmune disorder that selectively targets neuromuscular junctions. The potential application of pluripotent stem cell (PSC) - derived neurons in regenerative medicine and disease modelling ideally requires their integration into complex functional human networks or tissues. Yet, one of the most important properties of neurons, namely their ability to form functional synapses and transmit information to appropriate downstream targets, remains largely unexplored in human organoids and other PSC-based model systems. In the present study, the researchers aimed at establishing a neuromuscular model by in vitro co-culturing of human PSC derived into spinal motorneurons and human myoblast-derived skeletal muscle. The disease was modelled by incubating these co-cultures with autoantibodies from myasthenia gravis patients. The model was shown to be able to simulate muscle contraction under the control of the neurons. Further, the data showed a reversible reduction in the amplitude of muscle contractions when using the autoantibodies. In conclusion, this neuromuscular junction assay has a significant potential for modelling neuromuscular diseases and regeneration.
Functional connectivity under optogenetic control allows modeling of human neuromuscular disease
Lorenz Studer, Julius A. Steinbeck
Added on: 10-28-2021
Tunable hydrogels to study cell invasion
November 2015
University of Toronto, Toronto, Canada
The study describes the development of tunable hydrogels whose mechanical and chemical properties are modified to study the cell invasion mechanisms of human cancer cell lines. The results show that the presence of matrix metalloproteinases cleavable peptides increases cell invasion. These extracellular matrix mimetic hydrogels show that by tuning the microenvironmental properties it is possible to recapitulate variable tissue properties to study cell invasion.
Tuning the microenvironment: click-crosslinked hyaluronic acid-based hydrogels provide a platform for studying breast cancer cell invasion
Molly S Shoichet
Added on: 07-31-2021
3D microfluidic model for anti-metastatic drug screening
October 2015
Massachusetts Institute of Technology, Cambridge, USA
In this study, a microfluidic device recapitulating tumor microenvironment was developed by co-culturing cancer cell aggregates in 3D scaffolds with human umbilical vein endothelial cells to perform drug screening of epithelial-to-mesenchymal inhibitors against metastatic processes. The results showed that the presence of endothelial cells in different compartments induced cell dispersal of lung adenocarcinoma cells, which could be inhibited with all drugs tested. Contrary, none of the inhibitors could completely block bladder carcinoma cells dissemination, but the use of all the drugs combined almost could. However, this effect was inhibited with direct co-culture with human endothelial cells through growth factors signalling. Overall, the researchers provide a new 3D microfluidic platform that simulates in vivo microenvironments to perform drug screening and design effective therapeutical strategies.
Identification of drugs as single agents or in combination to prevent carcinoma dissemination in a microfluidic 3D environment
Roger D Kamm
Added on: 11-27-2021
Biofabrication of 3D model to study bone marrow metastasis
October 2015
The George Washington University, Washington, USA
The study presents the modelling of bone marrow metastatic invasion by breast cancer cells with a 3D-printed hydrogel matrix that mimics bone marrow microenvironment. The co-culture of human bone-marrow-derived mesenchymal stem cells and human breast cancer cells in this matrix is able to recapitulate morphological and migratory properties of breast cancer bone invasion. This shows that this model can be useful for other researcher to model metastasis.
3D printed nanocomposite matrix for the study of breast cancer bone metastasis
Lijie Grace Zhang
Added on: 07-12-2021
Breast cancer metastasis suppressor 1 inhibits cell invasion in breast cancer cells
October 2015
Konyang University, Daejeon, South Korea
Epithelial-to-mesenchymal transition is a critical step in cancer metastasis. Breast cancer metastasis suppressor 1 has been identified as a metastasis suppressor, but the underlying mechanisms that attenuate cancer cell metastatic transformation remain unknown. Here, human breast cancer cell lines were used to investigate the molecular interactions that drive the suppression of cancer cell metastatic behaviour induced by Breast cancer metastasis suppressor 1 activity. The results showed that Breast cancer metastasis suppressor 1 strongly inhibited TGF-beta1 induced epithelial-to-mesenchymal transition and cell invasion. Moreover, other cell invasion-related genes were downregulated by Breast cancer metastasis suppressor 1 as a consequence of the reduced TGF-beta1 induced expression of a transcription regulator. Finally, the signalling mechanism by which Breast cancer metastasis suppressor 1 affects transcriptional activity was elucidated. Overall, the researchers describe the signalling cascade by which Breast cancer metastasis suppressor 1 inhibits cancer cell invasion features in breast cancer cells.
Breast cancer metastasis suppressor 1 (BRMS1) attenuates TGF-β1-induced breast cancer cell aggressiveness through downregulating HIF-1α expression
Hoi Young Lee
Added on: 10-30-2021
Development of a 3D breast cancer culture platform for drug screening
October 2015
Kyoto University, Kyoto, Japan
3D models are emerging as dynamic models with high value to study cell growth and proliferation. Nowadays, coupled 3D modelling and imaging techniques offer easy-to-use systems. To study anti-cancer drugs, a simple visualization setup to image non-proliferative cells is needed. Here, a fluorescent-based assay is used to analyze cell proliferation of human breast cancer cells in a 3D model using a pulse-labelling technique with protein Kaede. The results show that it was possible to analyze the effects of 5-fluorouracil and PD0332991 anti-cancer drugs in human breast cancer cells. Overall, the researchers present a newly developed platform to easily study anti-cancer drug effects on cell proliferation to be able to do fast drug screening assays in human cells cultured in 3D conditions.
Data of a fluorescent imaging-based analysis of anti-cancer drug effects on three-dimensional cultures of breast cancer cells
Junji Itou
Added on: 10-31-2021
In vitro tests of prostate cancer patients immune cells to improve prognosis
October 2015
Umeå University, Umeå, Sweden
In colorectal cancer (CRC) and prostate cancer (PC) the immune response may have contrasting effects on patient prognosis. In CRC, increased infiltration of macrophages is strongly associated with an improved prognosis while the opposite is true in PC. In this study, the researchers evaluated the distribution and prognostic value of different sets of macrophages in a cohort of 234 PC patients. Results show a significantly different ratio in PC compared to CRC patients with a correlation with prognosis. Researchers further used an in vitro cell culture model of tumour-activated macrophages (TaMs). The results support the importance of a “good inflammatory response” in the prognosis of CRC patients and suggest that manipulations of the macrophage phenotype may be important in the development of new treatment strategies in PC and other cancers where immune infiltration is generally linked to poor prognosis.
Secreted factors from colorectal and prostate cancer cells skew the immune response in opposite directions
Sofia Edin
Added on: 07-28-2021
New tool to isolate circulating tumor cells
October 2015
University of Southern California, Los Angeles, USA
To be able to capture circulating tumor cells, a method is presented in this study, combining epithelial cell adhesion molecule immunomagnetic separation with a fluorescence-activated cell sorting. When applying this method to diverse cultured human breast cancer cell lines or to human peripheral blood samples, it was possible to efficiently recover cells from all intrinsic subtypes of breast cancer except for claudin-low cell lines. The transcriptomic profile of isolated cells from cell lines was highly correlated to the bulk cell line expression signature but not to the peripheral blood isolated cells. This method allows for isolation and high-quality RNA isolation of circulating tumor cells to perform a specific subtype analysis.
EpCAM based capture detects and recovers circulating tumor cells from all subtypes of breast cancer except claudin-low
Julie E Lang
Added on: 07-31-2021
Stromal-epithelial interactions in a 3D model of breast cancer
October 2015
University of North Carolina at Chapel Hill, Chapel Hill, USA
A multicellular organoid 3D system using human breast cancer cells and human fibroblast is used to study cell motility patterns with optical coherence tomography. The results show that the density of stromal cells affects several parameters of mammary cell motion and how to visualise hyperspectral data to observe heterogeneity within organoids. Overall, this study presents a new tool to image cellular functional changes with optical coherence tomography.
Inverse-power-law behavior of cellular motility reveals stromal–epithelial cell interactions in 3D co-culture by OCT fluctuation spectroscopy
Amy L Oldenburg
Added on: 07-27-2021
3D model to study tumor resistance mechanisms
2015
University of Buenos Aires, Buenos Aires, Argentina
A new model based on culturing a HER2 overexpressing human mammary adenocarcinoma cell line as spheroids is used in this study to understand the role of tumor self-organization in Trastuzumab resistance. Compared to monolayer cultures, the efficacy of Trastuzumab was greatly reduced in the spheroids, as confirmed by the reduction in apoptosis. This was linked to an induction of autophagy, seen to be protective. Thus, this model helped to elicit key insights of drug resistance in tumor cells, showing that it can be a valuable tool to study antitumor therapies and improve their efficacy.
Autophagy protects from Trastuzumab-induced cytotoxicity in HER2 overexpressing breast tumor spheroids
Gabriel L Fiszman
Added on: 08-02-2021
Engineered patients' T cells to target human papillomavirus positive cancer cells
2015
National Cancer Institute, Bethesda, USA
The human papillomavirus (HPV) E6 and E7 oncoproteins are constitutively expressed by HPV+ cancers and they are absent from healthy tissues, making them ideal targets for immunotherapy using T cells. However, poor results of early clinical trials have shown that HPV+ tumor cells possess diverse means of immune evasion. In the present study, the researchers have genetically engineered tumor-infiltrating T cells from an HPV+ cancer patient to express an oncoprotein-specific TCR and tested for specific reactivity against HPV+ epithelial tumor cells. Engineered cells showed great affinity specifically to HPV+ cells and a capacity to kill them. The study demonstrates that HPV+ tumours can be targeted by E6 specific T cell receptor gene engineered T cells, and they provide the foundation for a novel cellular
therapy directed against HPV+ malignancies.
Targeting of HPV-16+ epithelial cancer cells by TCR gene engineered T cells directed against E6
Christian S. Hinrichs
Added on: 09-14-2021
Computational discovery of transcriptional regulators in cancer
2015
National Institute of Genomic Medicine, Mexico City, Mexico
Implementation of a series of algorithms to analyze gene regulatory networks and transcriptional regulators in the context of breast cancer is presented. By analyzing 880 microarrays of biopsy samples from primary breast cancer, it was possible to describe several master regulators involved in well-known hallmarks of cancer. Overall, this study shows that these techniques could be a potential tool to understand the first stages of cancer development.
Transcriptional master regulator analysis in breast cancer genetic networks
Enrique Hernández-Lemus
Added on: 07-31-2021
Hydrogel-based 3D model of breast cancer
2015
Brown University, Providence, USA
A hydrogel-based 3D model with human breast cancer cells is used to try to reproduce human breast tumour self-organisation and differentiation in different microtissues. When compared to a 2D model, this new model shows differential expression of different microtissue markers, which remain responsive to estrogen when exposed to 17β-estradiol. This study describes a 3D model that is more physiological than 2D models to study human breast cancer.
MCF-7 human breast cancer cells form differentiated microtissues in scaffold-free hydrogels
Kim Boekelheide
Added on: 07-29-2021
miRNA-144 promotes radiotherapy resistance of breast cancer cells
2015
The Second Hospital of Jilin University, Changchun, China
Resistance to anti-cancer therapies is a critical complication in patients with breast cancer. miRNAs can influence several cancer-related biological processes, including responses to treatments. Here, human breast cancer cells are used to investigate the role of miRNA-144 in radiotherapy sensitivity and cell migration and invasion. The results showed that overexpression of miRNA-144 had a positive effect on cancer cell proliferation and increased cancer cells resistance to radiotherapy. Moreover, the modulation of miRNA-144 expression affected migration and invasion capabilities of cancer cells and its overexpression led to E-cadherin downregulation and Snail upregulation. Finally, miRNA-144 was found to activate AKT in breast cancer cells. Overall, the researchers suggest that miRNA-144 has a crucial role in tumorigenesis and breast cancer progression, which could make it a potential target for new therapeutic strategies.
MicroRNA-144 affects radiotherapy sensitivity by promoting proliferation, migration and invasion of breast cancer cells
Xiaojing Jia
Added on: 10-31-2021
Oral cancer patients' tissue analysis to understand immune response
2015
Meikai University of School of Dentistry, Saitama, Japan
Oral leukoplakia is a premalignant lesion of the oral mucosa, it has been shown that a subtype of patients has an increased risk for malignant transformation. Numerous studies have shown the role of tumor-associated macrophages (TAMs) to potentially initiate and promote tumorigenesis and a correlation with an abundance of TAMs and poor prognosis for many cancer patients although the claim was contradicted in other cancers. In the present study, the researchers aimed at identifying the phenotype of TAMs in leukoplakia. Tissues were isolated from patients and analyzed by immunohistochemistry. The study shows an increase in the rate TAM infiltration was observed in mild and moderate leukoplakia which positively correlated with the expression of two markers specific for macrophages with the capacity to disrupt tissue architecture. Hence, the study sheds more light on the cascade of immunological events leading to malignant transformation.
Tumor-associated macrophages in oral premalignant lesions coexpress CD163 and STAT1 in a Th1-dominated microenvironment
Yoshihiro Ohmori
Added on: 09-15-2021
Predictive model of breast cancer lymph node invasion
2015
Seoul National University Hospital, Seoul, South Korea
Luminal A breast cancer can have early complications leading to the development of lymph node metastasis. However, the methods of detection of this process are unreliable and some false negative cases have been reported. Here, a biomarker-based model is developed to predict lymph node metastasis in luminal A breast cancer using tissue samples of patients of luminal A invasive ductal carcinoma to investigate the expression of silent mating type information regulation 2 homolog 1 and apoptosis-related factors. The results showed that a combination of different specific factors of clinical and transcriptomic data had the strongest prediction performance for lymph node invasion, which also could predict shortened disease-free survival. Furthermore, it was elucidated that silent mating type information regulation 2 homolog 1 and specific apoptosis-related proteins have tumor suppressor activity in luminal A breast cancer. Overall, the researchers present a new tool that can help improve the prediction of lymph node metastasis, which can have a great impact in optimizing surgical strategies in breast cancer patients.
Expression of SIRT1 and apoptosis-related proteins is predictive for lymph node metastasis and disease-free survival in luminal A breast cancer
Han Suk Ryu, Seock-Ah Im
Added on: 10-25-2021
3D multicellular microfluidic system to study tumor microenvironment
2015
Seoul National University Hospital, Seoul, South Korea(1)
University of Pennsylvania, Philadelphia, USA(2)
University of Pennsylvania, Philadelphia, USA(2)
A new model based on a compartmentalized 3D microfluidic device is developed to mimic cancer tissue microarchitecture. By combining human breast tumor spheroids with human mammary gland epithelial cells and breast fibroblasts, the microenvironment of mammary gland carcinoma could be mimicked. Using this platform, the anticancer drug paclitaxel was tested in a highly complex "in vitro" model and the anticancer effects observed "in vivo" could be reproduced. Thus, this new platform can be a very useful tool to study the tumor microenvironment and to explore potential therapeutic agents.
A microengineered pathophysiological model of early-stage breast cancer
Woo Kyung Moon(1), Dongeun Huh(2)
Added on: 08-02-2021
Analysis of cancer antigen expression in colorectal cancer patients' tissues
2015
Mount Sinai Roosevelt Hospital Center, New York, USA
Although surgery remains the main means of treating colorectal cancer patients, 40% of patients develop metastatic disease after surgery which prompts the need for new anti-cancer agents. IGF2BP3 (IMP3) is an mRNA binding protein present only in testis at adult age with increased expression in cancer patients. In the present study, the researchers wanted to determine if IGF2BP3 had potential as a vaccine target. Data were collected prospectively from CRC patients in an IRB-approved tissue and data bank. Patients' tissues were analyzed quantitatively for expression levels of IGF2BP3 in tumors and testis. Protein expression was assessed by immunocytochemistry. IGF2BP3 mRNA was overexpressed in 43% of the tumors whereas the protein was noted in 50% of samples. No correlation was seen between mRNA expression and disease severity. This protein represents a potential vaccine target, however, further research is needed.
Expression of the cancer testis antigen IGF2BP3 in colorectal cancers; IGF2BP3 holds promise as a specific immunotherapy target
Richard L. Whelan
Added on: 09-18-2021
Developing a new 3D model to test antitumor nanodrugs in vitro
2015
Russian Academy of Sciences, Moscow, Russia
A new system of encapsulated microtumor spheroids of human breast cancer cells was developed to study nanosize antitumor drugs. In comparison to a 2D monolayer culture, these new microcapsules appear to be more resistant to nanosize formulations and, thus, are a potential new tool for drug testing.
Microencapsulated multicellular tumor spheroids as a tool to test novel anticancer nanosized drug delivery systems in vitro
Elena A. Markvicheva
Added on: 07-11-2021
Docosahexaenoic acid anti-cancer mechanisms in breast cancer cells
2015
University of Oklahoma Health Sciences Center, Oklahoma City, USA
In recent years, Docosahexaenoic acid has been shown to have anti-tumoral activity and is being tested for breast cancer treatments. However, its anti-cancer mechanisms remain unclear. The tumor microenvironment has an essential role in cancer progression and exosomes have been identified as essential mediators in promoting angiogenesis, but there is little knowledge on their exact contribution or whether they can modulate Docosahexaenoic acid anticancer activity. Here, human breast cancer cell lines were treated with Docosahexaenoic acid to investigate the role of exosomes in Docosahexaenoic acid-mediated anticancer activity and co-cultured with human endothelial cells to explore its anti-angiogenesis role. The results showed increased exosome secretion with microRNAs altered levels after treatment of cancer cells. Those mostly overexpressed were identified to have anti-cancer properties and were overexpressed also in exosomes of different Docosahexaenoic acid-treated breast cancer cell lines, but not in normal breast cells. Finally, co-culture of Docosahexaenoic acid-treated breast cancer cells with endothelial cells induced increased levels of the same microRNAs in endothelial cells, in which they reduced pro-angiogenic genes expression and inhibited tube formation. Additionally, the anti-angiogenic activity could be reversed with the knockdown of genes related to exosome secretion. Overall, the researchers demonstrate that Docosahexaenoic acid treatment disrupts angiogenesis capabilities of breast cancer cells through the modulation of microRNAs rich exosomes, which could lead to new anti-cancer targets and further validate Docosahexaenoic acid for cancer treatment.
Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA)
Wei-Qun Ding
Added on: 11-01-2021
Isolation of anti cancer antibodies from lung cancer patients' sera
2015
Duke University Medical Center, Durham, USA
The majority of tumors in lung cancer are detected at an advanced stage when treatment options are limited. There is a clear need for a greater number and wider variety of effective therapies. In the present study, the researchers explored the possibility of taking cues from the immune response to tumors, particularly in patients who have an early-stage disease and never develop recurrence. Complement factor H (CFH) is one of a class of complement inhibitory factors that protect both normal and tumor cells from attack and destruction by the immune system. The researchers isolated autologous antibodies against CHF from cancer patients serum. The antibodies were then tested in vitro and it was shown that they have the capacity to neutralize cancer cell lines. This work suggests that autoantibodies against CHF may perform killing cancer in vivo as well. The development of specific antibodies to the conformationally distinct epitope of CFH may lead to a useful biologic therapy for lung cancer.
Complement factor H antibodies from lung cancer patients induce complement-dependent lysis of tumor cells, suggesting a novel immunotherapeutic strategy
Edward F. Patz
Added on: 09-14-2021
Matrix stiffness for tissue-specific cancer stem cell growth
2015
University of South Carolina, Columbia, USA
In this study, tunable hydrogels were used to find the optimum matrix stiffness for tissue-specific cancer stem cells growth. Different human cancer cell lines were cultivated on different 3D scaffolds and it was found that cancer stem cells from different origins have different optimum matrix stiffness. Additionally, it was possible to investigate the associated gene expression to the optimum cancer stem cell conditions, showing that this model can be useful to study cancer stem cell microenviornments and dynamics.
Optimum 3D matrix stiffness for maintenance of cancer stem cells is dependent on tissue origin of cancer cells
Esmaiel Jabbari
Added on: 07-31-2021
Personalized breast cancer therapy screening
Company 2015
SpheroTec GmbH, Munich, Germany
SpheroTest uses tumor tissue from each individual patient to produce personalised 3D tumor spheroids that are subjected to different cancer medications. Breast cancer patients who took the drug identified as effective with SpheroTest as planned had a tumor freedom rate of over 50%, twice as high as that of patients whose therapy was selected only on the basis of statistical experience without SpheroTest. SpheroTest was able to reliably determine the effective drug for 94% of the patients. Studies on other types of cancer are still ongoing or are in the evaluation.
Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy - the SpheroNEO study.
Barbara Mayer
Added on: 05-22-2020
3D multicellular model to study the interactions between tumors and their microenvironment
Company 2015
Roche Innovation Center Penzberg, Penzberg, Germany
There is growing evidence that tumor microenvironment is a crucial element for tumor progression. Fibroblasts are the most abundant cells in tumor microenvironment and are key for tumor support, growth and metastasis. Thus, there is a need for in vitro models that can reproduce these features to investigate the mechanisms underlying these interactions. However, the 2D models currently available poorly represent this cross-talk. Here, a new 3D co-culture model is developed to study the direct cell-cell interplay between different human cancer cell lines and human fibroblasts or tumor-associated fibroblasts. The results showed that the co-culture of these cells increased the proliferation of several cancer cell lines and induced the expression of soluble factors in a cancer type-specific manner. The use of antibodies that impeded the function of these factors inhibited the increased cell proliferation of the co-cultures. Moreover, the presence of tumor-associated fibroblasts modified the response to therapeutic agents. In this study, the researchers develop a new model that replicates the support that fibroblasts provide for the tumor cells. The model can be used to study key mechanisms in the interactions between tumors and their associated microenvironments.
Fibroblasts influence survival and therapeutic response in a 3D co-culture model
Meher Majety
Added on: 10-03-2021
Human ex vivo skin samples used for microspectroscopic studies in psoriasis
2015
Centre hospitalier universitaire de Québec, Québec, Canada
Psoriasis is a chronic dermatosis which affects approximately 3% both men and women worldwide whatever their age. The etiology of this autoimmune pathology modulated by genetic, immunologic, and environmental factors but ultimately still poorly understood. In the present study, the researchers aimed at understanding better lipid and protein organization of psoriasis patients as this is understanding is essential to develop therapeutic strategies. Interestingly, infrared and Raman microspetroscopic studies on skin samples from donors revelead disordered structures of lipids and proteins in psoriasis patient. However, the authors stress that the psoriasis samples came from deceased patients and the healthy samples from breast cancer surgery. In the future, the study should be repeated with using samples with more consistent and comparable origin. Still, the differences seen could indicate major problems at the molecular level in psoriasis skin.
Using infrared and Raman microspectroscopies to compare ex vivo involved psoriatic skin with normal human skin
Gaétan Laroche
Added on: 10-18-2021
Identification of relevant biomarkers for lung cancer to improve prediction
2015
University of Michigan, Ann Arbor, USA
Knowledge of the molecular alterations and immune microenvironment present in lung cancer have allowed patients' stratification according to their outcome and the identification of new targets for therapy development. Still, novel biomarkers are needed to predict patients prognosis and therapy response. MAP3K3 is an enzyme involved in both the immune response and tumor progression. In this study, the researchers studied in vitro the roles of MAP3K3 in cell proliferation, migration, invasion and effects on cell cycle following MAP3K3 knockdown using short interference RNA in lung cancer cell lines. Further, the researchers analyzed the MAP3K3 protein/mRNA expression in primary lung cancers and its association with clinical-pathological characteristics including patient survival. Results indicate that MAP3K3 overexpression correlates with an active immune response in the tumor environment in parallel with improved patient survival. MAP3K3 may potentially not only serve as a diagnostic/prognostic marker for patients with lung cancer but also provide an indicator for future investigations into immunomodulatory therapies for lung cancer.
MAP3K3 expression in tumor cells and tumor-infiltrating lymphocytes is correlated with favorable patient survival in lung cancer
Guoan Chen
Added on: 07-28-2021
Prostacyclin enhances breast cancer cell migration
2015
University of South Australia, Adelaide, Australia(1)
University of Sydney, Sydney, Australia(2)
University of Sydney, Sydney, Australia(2)
Metastasis is the most fatal complication in cancer patients. Upregulation of COX-2 and its downstream prostaglandins is usually observed in cancer patients and has been linked to metastasis. Some prostaglandins mechanisms have been already identified, but there are others whose roles remain elusive. Here, human cancer cells and a human breast cancer cell line overexpressing COX2 were used to evaluate the pro-migratory mechanisms of specific prostaglandins. The results showed that the inhibition of prostacyclin and prostaglandin synthases inhibited cell migration, which could be rescued by treating cancer cells with a prostacyclin analogue. Moreover, only pharmacological IP receptor knockdown decreased cell migration and expression of pro-migratory genes in COX2 expressing human breast cancer cells, which matched with the enhanced migration in cancer cells with IP-activated receptors. Finally, the IP-dependent signalling pathway was identified to activate pro-migratory genes in COX2 overexpressing human breast cancer cells. Overall, the researchers elucidate signalling mechanisms of pro-migratory behaviour through prostacyclin IP receptor activation in COX2 overexpressing breast cancer cells that could lead to novel therapeutic targets to hinder tumor progression.
Pro-migratory actions of the prostacyclin receptor in human breast cancer cells that over-express cyclooxygenase-2
Nenad Petrovic(1), Michael Murray(2), Sarah E Allison(2)
Added on: 11-01-2021
Antibody treatment for triple-negative breast cancer
2015
University College Dublin, Dublin, Ireland
Nowadays, it is urgent to find an effective therapy targeted to triple-negative breast cancer. Current knowledge points towards epidermal growth factor receptor as a driver gene of the disease. Therefore, investigating the activation mechanisms of this gene could identify new targets for potential therapies. One of them could be ADAM-17, as the activation of the epidermal growth factor receptor depends on its mediated release of certain ligands. Here, a monoclonal antibody targeting ADAM-17 is tested in different human breast cancer cell lines cultured in different setups. The results show that the antibody significantly decreases epidermal growth factor receptor downstream signalling, reduces the proliferation of cancer cells in 2D and 3D conditions and induces cancer cell death. Moreover, it also inhibited cancer cell invasion and migration. In this study, the researchers validate the anticancer activity of an ADAM-17-directed antibody in different models of human breast cancer, which can potentially open the door to new opportunities in triple-negative breast cancer therapies.
Targeting ADAM-17 with an inhibitory monoclonal antibody has antitumour effects in triple-negative breast cancer cells
F Caiazza
Added on: 10-15-2021
Generation of a high throughput 3D spheroid tumor model
2015
Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany
Natural killer (NK) cells rapidly recognize and destroy malignantly transformed cells. Due to their natural ability to lyse tumor cells without prior sensitization, NK cells hold promise for cancer immunotherapy although tumor immune escape strategies might compromise NK cell activity. In the present study, the researchers generated an in vitro, high throughput 3D tumor spheroid model from human cervical carcinoma cell lines to study NK cell infiltration and immunosurveillance. The model allows for long-term observation of cell proliferation, NK cell infiltration and NK cell cytotoxicity and antitumor efficacy. Further, the model allows for isolation of the cells that manage to infiltrate the tumor mimicking spheroid. The model can be used for donor selection of cytotoxic lymphocytes, status quo determination of antitumor immunoreactivity, and preconditioning of a cancer patient prior to allogeneic cellular immunotherapy and thus help to personalize treatment.
Cytotoxicity and infiltration of human NK cells in in vivo-like tumor spheroids
Joachim Koch
Added on: 09-15-2021
Generation of adoptive immune therapy against cancer in GMP conditions
Regulatory accepted 2015
Ludwig-Maximilians-University, Munich, Germany
NY-ESO-1 antigens are expressed in a variety of solid tumors but are absent in mature healthy tissues. In this study, the researchers developed a procedure to generate immune CD4C TH1 cells for the clinic targeting specifically NY-ESO-1 cancer cells. Cells were extracted from the peripheral blood of healthy donors and were then subject to in vitro sensitization by stimulating with peptides of NY-ESO-1. T cells were isolated and subsequently expanded. The manufactured cells could induce cell cycle arrest and apoptosis in tumor cell lines. The protocol is GMP grade and approved by the regulatory authorities.
Rapid generation of NY-ESO-1-specific CD4+ Thelper1 cells for adoptive T-cell therapy
Tobias Feuchtinger
Added on: 07-28-2021
Lung pericytes modulate microvessel structures
2015
University of Bern, Bern, Switzerland
Angiogenesis is a complex tissue-specific event that has a crucial role in several biological processes. However, in vitro models have important limitations in reproducing angiogenesis and vascular remodelling. Here, a 3D in vitro human lung microvasculature model was developed using primary human lung pericytes from lung cancer patients co-cultured with human umbilical cord vein endothelial cells to investigate mechanisms related to vascular regulation. The results showed that microvessels formed and remained stable for 14 days. Moreover, paracrine signalling from lung pericytes was essential for normal perfusion. The pericytes migrated toward endothelial microvessels establishing cell-cell communication and vascular-related structures. Furthermore, direct contact of pericytes and endothelial cells led to decreased permeability, a more regular microvessel architecture and to vasoconstriction response after phenylephrine treatment. Overall, the researchers develop a biomimetic platform to study the importance of pericytes on microvascular modulation and potentially investigate the changes induced by patient-derived cells in a physiologically relevant context.
Primary human lung pericytes support and stabilize in vitro perfusable microvessels
Thomas Geiser, Olivier T Guenat
Added on: 11-02-2021
Organotypic model for cancer drug screening
2015
Instituto Mexicano del Seguro Social, Monterrey, Mexico
Breast cancer is the most prevalent cause of cancer-related death in women worldwide. Despite the recent advances, there is still an urge to find efficient antitumour compounds with fewer adverse effects. Thus, better translational models are needed to perform more accurate drug screening and testing assays. Here, a new method is established to generate organotypic cultures of human breast tumour slices to assess the antineoplastic potential of several natural compounds. The results showed that the explants could be successfully cultured. Additionally, drug tests showed that paclitaxel alone could decrease explant viability, while natural compounds showed diverse effects. However, when combining paclitaxel with natural compounds, there was a synergistic effect of the drugs. Overall, the researchers establish a new methodology to perform an organotypic culture of human breast tumour slices to test ex vivo antitumour compounds.
Organotypic culture of breast tumor explants as a multicellular system for the screening of natural compounds with antineoplastic potential
Pilar Carranza-Rosales
Added on: 10-13-2021
RNA interference could be used to abrogate immunosuppression in prostate cancer
2015
Beckman Research Institute at City of Hope, Duarte, USA
Prostate cancer is a most common malignancy in men with little efficacy of standards of care once it reaches metastatic stage which underlines the importance of developing new treatment strategies such as immunotherapy. Human tumors recruit and expand populations of potently immunosuppressive myeloid-derived suppressor cells (MDSCs) which were associated with progression and poor patients’ survival. In the present study, the researchers have evaluated myeloid cell populations using flow cytometry on blood samples from patients followed by ex vivo functional assays. A population of granulocytic MDSCs that accumulate in patients’ circulation during prostate cancer progression was identified and shown to potently inhibit autologous T cells proliferation. The circulating MDSCs have high levels of activated STAT3, which is a central immune checkpoint regulator. Using RNA interference technology, the researchers were able to shut down the level of STAT3 and abrogate the immunosuppressive effects of patients-derived MDSCs on T cells. The study demonstrates the accumulation of granulocytic MDSCs with prostate cancer progression and the feasibility of using TLR9-targeted STAT3 siRNA delivery strategy to alleviate MDSC-mediated immunosuppression.
TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients
Sumanta K. Pal, Marcin Kortylewski
Added on: 09-14-2021
Automated HER2 assesment in breast cancer
2015
Pathology Friesland, Leeuwarden, Netherlands
Validation of a fully automated "in situ" hybridisation procedure combined with an automated imaging system for HER2-targeted therapy. It was possible to assess HER2 over 328 samples of breast tumour patients and, when compared to previous manual methods, the method showed to have a consistent efficacy. This platform can facilitate the routine assessment of HER2 in breast cancer patients for clinical purposes.
Fully automated fluorescent in situ hybridization (FISH) staining and digital analysis of HER2 in breast cancer: a validation study
Elise MJ van der Logt
Added on: 07-29-2021
Microfluidic 3D co-culture system to study lymphatic microenvironment
2015
École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Several types of cancers disseminate through the lymphatic system, but the mechanisms that lead to this phenomenon are poorly understood. Biophysical characteristics of the lymphatic tissue can affect cell behaviour and may have a key role in cancer cell transendothelial migration. Microfluidic systems are a popular tool to model complex tissues in vitro, however, there is still room for further development of the technique. Here, a microfluidic device is developed to combine 3D co-culture of human lymphatic endothelial cells and breast cancer cells with advanced control of the biophysical cues present in the lymphatic microenvironment. This model can be used in a medium-throughput setup to perform quantitative analyses. The results showed that luminal flow increases tumor cell transmigration by modulating lymphatic endothelial cells. Furthermore, transmural flow increased intravasation. Overall, the researchers propose a new model that can recapitulate the complexity of the lymphatic microenvironment in the context of tumor metastasis and can be used to elucidate the mechanisms regulated by different biophysical features of the tissue.
An in vitro model of the tumor–lymphatic microenvironment with simultaneous transendothelial and luminal flows reveals mechanisms of flow enhanced invasion
Melody A Swartz
Added on: 10-09-2021
New biofabrication approach for 3D culture
2015
University of California San Diego, La Jolla, USA
Here, they use a new biofabrication approach to generate hydrogel structures that enable long-term maintenance of spheroids. The authors validate this method with breast cancer spheroids and embryoid bodies derived from induced pluripotent stem cells.
Nonlinear 3D projection printing of concave hydrogel microstructures for long-term multicellular spheroid and embryoid body culture
S C Chen
Added on: 07-03-2021
Transcriptomic profile of metastasis biopsis during treatment
2015
Karolinska Institutet and University Hospital, Stockholm, Sweden
During a phase III clinical trial, a series of breast tumor samples were extracted from a group of volunteer patients. It was possible to obtain high-quality transcriptomic data from most of the patients. The monitoring of gene expression showed differences in the profiles of patients undergoing monotherapy versus those who were getting combined therapy and these correlated with what could be seen with conventional radiology assessments. This showed that transcriptomic profiling can be done in longitudinal studies and gave new insight into relevant biological processes related to the treatment.
Gene expression profiling of sequential metastatic biopsies for biomarker discovery in breast cancer
Theodoros Foukakis
Added on: 07-31-2021
Combinatorial approach using ex vivo patients immune cells to kill cancer cell lines
2015
University of Pennsylvania, Philadelphia, USA
HER 2/neu (HER2) is a receptor with phosphorylation activity that is amplified in a number of solid malignancies and is involved in early uncontrolled growth, enhanced invasiveness, and metastatic spread. HER2-targeted monoclonal antibodies show great results but significant resistance to therapy can occur. In the present study, the researchers used immune cells isolated from patients and sensitized ex vivo to assess their capacity to recognize and kill human cancer cell lines expressing HER2 in combination with other treatments. The results show that combinatorial strategy using immune cells engineered to target different epitopes of HER2 together with antibody treatment may be the best approach to be developed for clinical trials.
CD4+ T-helper type 1 cytokines and trastuzumab facilitate CD8+ T-cell targeting of HER2/neu–expressing cancers
Brian J. Czerniecki
Added on: 09-14-2021
Generation of novel immunotoxin to treat blood cancer via phage display
2015
Justus-Liebig-University Giessen, Giessen, Germany(1)
University Hospital RWTH Aachen, Aachen, Germany(2)
University Hospital RWTH Aachen, Aachen, Germany(2)
The current chemotherapy treatment for acute myeloid leukaemia (AML) has several drawbacks. More specific and efficient approaches are therefore required to eradicate completely malignant cells while leaving healthy cells unaffected. In this study, the researchers generated antibodies that bind specifically to the surface of AML blast cells and AML bone marrow biopsy specimens. The antibodies were isolated from an available library by phage display and tested in vitro for internalization. Engineering the selected antibody into an immunotoxin, it was tested on a leukaemia cell line for control of cell proliferation and the induction of apoptosis. This method may therefore be useful for the selection of novel disease-specific internalizing antibody fragments, providing a novel immunotherapeutic strategy for the treatment of AML patients.
Phage display-based generation of novel internalizing antibody fragments for immunotoxin-based treatment of acute myeloid leukemia
Mehmet Kemal Tur(1), Stefan Barth(2)
Added on: 07-28-2021
In vitro knockdown of cancer marker shows promises for therapy development
2015
Sichuan University, Chengdu, China
Lung cancer is the leading cause of cancer-related mortality with high incidence rates, metastatic propensity, and acquired resistance to therapy. Many studies have shown that the pituitary tumor-transforming gene (PTTG) is an oncogene that is overexpressed in a variety of tumors, however other studies suggest a negative correlation. In this study, the researchers aimed at clarifying if PTTG could be a marker for prognosis in lung adenocarcinoma cells. PTTG expression levels were assessed in human LAC tissues by an immunohistochemical assay using a tissue microarray procedure. Further, in vitro loss-of-function experiments were conducted to investigate the effects of PTTG on cell growth and invasive potential in LAC cell lines. Overall, PTTG1 protein expression was upregulated in LAC tissues and was positively associated with the lymphatic invasion of the tumor. The knockdown of PTTG expression inhibited tumor proliferation and invasion of LAC cells. The present findings suggest that PTTG may be a potential target for developing an effective immunotherapeutic strategy for LAC.
Knockdown of PTTG1 inhibits the growth and invasion of lung adenocarcinoma cells through regulation of TGFB1/SMAD3 signaling
Zheng-Rong Wang
W. H. Li et al. International Journal of Immunopathology and Pharmacology 2015 [868]
EURL ECVAM [869]
Added on: 09-14-2021
New immunotoxin design for potential treatment of breast cancer
2015
University of Notre Dame, Notre Dame, USA
Immunotoxins constitute a new type of cancer treatment. They are chimeric proteins comprising a specific cellular targeting domain linked to a cytotoxic factor. In the present study, the researchers designed, synthesized and used in vitro a novel immunotoxin with selective cytotoxic activity on ErbB2 positive cells, a marker overexpressed in the tumor cells of approximately 30% of breast cancer patients.
Design and evaluation of a peptide-based immunotoxin for breast cancer therapeutics
Shaun W. Lee
Added on: 07-27-2021
Tumour spheroids for drug screening
2015
Korea University, Seoul, South Korea(1)
Sogang University, Seoul, South Korea(2)
Sogang University, Seoul, South Korea(2)
Nanotechnology has arisen as a powerful tool to develop targeted therapies in cancer. However, the lack of reliable in vitro models limits the development of this technology. Here, human breast adenocarcinoma cells were cultured in 3D spheroids in arrays of concave microwells to test doxorubicin-loaded nanoparticles. The results showed that the loaded nanoparticles disrupted the small tumour spheroids, decreasing their size, but were ineffective against larger tumour spheroids. Moreover, those spheroids treated with doxorubicin-loaded nanoparticles were unable to preserve the circular shape. Finally, it was found that larger tumours had higher cell viability upon treatment and that the development of tight cell-cell junctions improved their drug resistance. Overall, the researchers present a new platform to model tumours in a 3D context where they develop resistance mechanisms potentially present in vivo. This opens the door to improved drug screening in cancer therapy.
Concave microwell array-mediated three-dimensional tumor model for screening anticancer drug-loaded nanoparticles
Sang-Hoon Lee(1), Bong Geun Chung(2)
Added on: 10-14-2021
Generation and testing of a novel immunotoxin against cancer in human cancer cell lines
2015
Instituto Politécnico Nacional, Yautepec Morelos, Mexico
The human epidermal growth factor receptors (ErbB or Her) are a family of four signal transduction proteins with intracellular domains that have tyrosine kinase
activity. Amplification or overexpression of Her2 disrupts normal cell control mechanisms and gives rise to aggressive tumor cells. In the present study, the researchers constructed an immunotoxin specific for Her2 and its cytotoxicity of probed in vitro on established human cancer cell lines. The generated immunotoxin displayed high cytotoxic capacities and could be a therapeutic candidate against Her2+ cancer.
Cytotoxic effect of the immunotoxin constructed of the ribosome inactivating protein curcin and the monoclonal antibody against Her2 receptor on tumor cells
Alma Leticia Martínez-Ayala
Lidia Patricia Jaramillo-Quintero et al. Bioscience, Biotechnology, and Biochemistry 2015 [874]
EURL ECVAM [875]
Added on: 07-28-2021
Inter-laboratory homogenization of Ki67 scoring
2015
University of British Columbia, Vancouver, Canada
To increase the homogeneity of Ki67 scoring results among different laboratories, researchers from18 laboratories were trained and tested through a web-based exercise to score Ki67 stained tissue microarray cases. This standardization procedure allowed for an increase in Ki67 reproducibility between these labs. This shows that using Ki67 as a biomarker could be a potential solution for breast cancer diagnostics, although future research is still needed to make it a reality.
An international study to increase concordance in Ki67 scoring
Torsten O Nielsen
Added on: 07-31-2021
3D multicellular microfluidic model of invasive ductal carcinoma in situ
2015
University of Wisconsin, Madison, USA
In recent years, there is growing knowledge about the transition from ductal carcinoma in situ breast cancer to metastatic cancers. However, the mechanisms underlying this process are poorly understood. Currently, available models are difficult to use and have severe limitations to recapitulate the main structure and functions of human ductal carcinoma in situ. Here, a microscale microfluidic model with human epithelial cells, human ductal carcinoma in situ cells and human mammary fibroblasts is developed to investigate the invasive transition of cancer cells. The results showed that this model recapitulates key structures and functions of ductal carcinoma in situ and allows to study cell-cell junctions and cell polarity. Moreover, the co-culture with human mammary fibroblasts induced invasive behaviour in ductal carcinoma in situ cells. In this study, the researchers propose a model that enables the formation of mammary ducts in a 3D environment and faithfully recapitulates the effects of ductal carcinoma in situ, opening the door to elucidate underlying mechanisms and the effects of microenvironmental factors of the invasive behaviour of ductal carcinoma in situ.
Microfluidic model of ductal carcinoma in situ with 3D, organotypic structure
Kyung E Sung, David J Beebe
Added on: 10-06-2021
Immune response to myeloma antigens vary with disease stage
2015
University of Heidelberg, Heidelberg, Germany
Multiple myeloma (MM) is a rarely curable malignant disease caused by the accumulation of cells in the bone marrow which displaces the normal composition of blood cells. In the present study, the researchers have assessed the concomitant expression of two antigens in myeloma cells purified from patients. Further, the researchers analyzed ex vivo the antigen-specific T-cell responses against these antigens using patients cells at different stages of the disease. They showed that specific T-cell responses in myeloma are triggered by antigen expression at an early stage but diminish and get suppressed with increasing tumor load during the evolution of the disease which underlines the necessity to take into account disease progression when developing immunotherapy.
Association of antigen-specific T-cell responses with antigen expression and immunoparalysis in multiple myeloma
Michael Hundemer
Added on: 09-14-2021
Markers identification in head and neck carcinoma patients' tissues
2015
Laboratorio de Biologia Molecular do Câncrer, Sao Paulo, Brazil
Head and neck squamous cell carcinoma (HNSCC) affects 600,000 new patients worldwide each year. The recent discovery of highly immunogenic and tumor-specific antigens called cancer-testis antigens (CTA) has opened new doors for specific tumor-targeted treatments using passive or active immunotherapeutic strategies. In this study, the researchers have used an in silico approach to select a subset of CTAs to be evaluated for expression in tissues from 89 HNSCC patients. Three CTAs were found in the vast majority of the tumors and also were associated with a poor outcome while another one was associated with disease-free survival. The study shows that the identification of human tumor antigens is important not only for the analysis of antitumor immune responses and the development of immunotherapies but also for the identification of molecular markers useful for diagnosis or prognosis.
A comprehensive expression analysis of cancer testis antigens in head and neck squamous cell carcinoma revels MAGEA3/6 as a marker for recurrence
André L. Vettore
Added on: 09-14-2021
Screening for anti-angiogenic drugs
2015
Massachusetts Institute of Technology, Cambridge, USA
This angiogenesis model utilizing AIM DAX-1 chips is used to investigate factors that are anti-angiogenic. The inhibitors may include chemical entities, proteins, genetic regulators, mechanobiological factors, etc. The device can be used to identify anti-cancer-drugs.
The microfluidic platform (termed the quantitative microfluidic angiogenesis screen, QMAS), that can monitor and quantify cellular behaviours, such as morphological changes, endothelial cell viability, and formation of angiogenic sprouts, depending on the various concentrations of drug applied. This model incorporates a perfusion culture-based system for generating stable concentration gradients in multiple 3D collagen matrices by generating a pressure-driven uniform flow rate through each of the microfluidic channels. These capabilities are demonstrated through a study of the drug bortezomib, known to inhibit angiogenesis in vivo.
A quantitative microfluidic angiogenesis screen for studying anti-angiogenic therapeutic assay
Roger D. Kamm
Added on: 07-09-2020
Tissue-based map of the human proteome
2015
KTH—Royal Institute of Technology, Stockholm, Sweden
Here, the researchers present a freely available interactive resource as part of the Human Protein Atlas portal (www.proteinatlas.org), offering the possibility to explore the tissue-elevated proteomes in tissues and organs and to analyse tissue profiles for specific protein classes. Samples representing all major tissues and organs (n = 44) in the human body have been analysed to generate a map of the human tissue proteome. This was achieved using quantitative transcriptomics on a tissue and organ level, combined with the profiling of the spatial localization of proteins down to the single-cell level. The study provides a global analysis of the secreted and membrane proteins and an analysis of the expression profiles for all proteins targeted by pharmaceutical drugs and proteins implicated in cancer.
Tissue-based map of the human proteome
Mathias Uhlén
Added on: 03-15-2023
3D model to investigate bone tissue cancer cell invasion
December 2014
The George Washington University, Washington, USA
Currently used in vitro models of breast cancer bone metastasis fail in reliably reproducing the complexity of cancer cell invasion, which involves several limitations that hinder the possibilities of reliably translating new findings to clinical applications. Here, a 3D biomimetic bone tissue model is developed using hydroxyapatite and induced human bone marrow mesenchymal stem cells within a chitosan hydrogel to culture or co-culture human breast cancer cells. The researchers were able to elucidate the best combination of nanocrystalline hydroxyapatite on chitosan scaffolds to maximise breast cancer cell adhesion and provide a platform that can reproduce biological interactions between cancer cells and the bone microenvironment. Furthermore, the results showed that the bone marrow mesenchymal stem cells could induce upregulation of metastasis-associated genes in breast cancer cells when co-cultured together. Overall, this study describes a new in vitro model that can replicate bone tissue microenvironment and opens the door to new therapeutical discoveries through the study of the mechanisms underlying breast cancer bone metastasis.
Engineering a biomimetic three-dimensional nanostructured bone model for breast cancer bone metastasis study
Lijie Grace Zhang
Added on: 10-26-2021
Expression of tissue compatibility marker analysed in grafted patients
December 2014
Fred Hutchinson Cancer Research Center, Seattle, USA
The transplantation barrier is defined by the HLA genes that are responsible for tissue histocompatibility. Mismatching of HLA-C for allotypes between patients and unrelated donors generally leads to very high risks of acute graft-versus-host disease (GVHD) and mortality after hematopoietic cell transplantation. Clinicians lack criteria for donor selection when HLA-C-mismatched donors are a patient’s only option for cure. Recently, the range of expression across HLA-C allotypes has been elucidated through the measurement of characteristic median fluorescence intensity (MFI) of cell surface expression. In the present study, the researchers used MFI to retrospectively analyze 1975 patients who had received a hematopoietic cell transplant. The association of outcome with the level of expression of patients’ and donors’ HLA-C allotypes was evaluated in multivariable models. The study showed that increased expression level of the patients’ mismatched HLA-C allotype was associated with increased risks of grades III to IV acute GVHD, nonrelapse mortality, and mortality. The immunogenicity of HLA-C mismatches in unrelated donor transplantation is influenced by the expression level of the patient’s mismatched HLA-C allotype. HLA-C expression levels provide new information on mismatches that should be avoided and extend understanding of HLA-C-mediated immune responses in human disease.
HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation
Effie W. Petersdorf
Added on: 09-19-2021
Isolation and cultivation of circulating tumor cells in pancreatic cancer
December 2014
University Hospital Kralovske Vinohrady, Prague, Czech Republic
This study investigated the feasibility of isolating and cultivating circulating tumor cells (CTCs) in pancreatic cancer (PaC) patients using a size-based filtration device. Peripheral blood samples were collected from 24 PaC patients prior to surgery and processed using a filtration device (MetaCell®), which isolates viable CTCs in an antibody-independent manner based on cell size. Captured cells were cultured on a membrane in nutrient-rich medium and examined via light and fluorescence microscopy. Histochemical and immunohistochemical analyses were performed to confirm cellular origin. CTCs were successfully detected in 16 patients (66.7%), independent of tumor stage, size, or metastatic status, and exhibited proliferative capacity and plasticity, with some cells invading the membrane. CTCs remained viable in vitro for at least 14 days, allowing for downstream applications. These results demonstrate the feasibility of isolating and cultivating viable CTCs from peripheral blood of PaC patients using a gentle, size-based filtration approach.
Circulating tumor cells in pancreatic cancer patients: Enrichment and cultivation
Vladimir Bobek
Added on: 05-14-2025
Cancer microfluidic 3D model to validate phototherapy strategies
November 2014
Stevens Institute of Technology, Hoboken, USA
Validation of a microfluidic 3D multicellular model of human breast cancer that allows the high-throughput testing of photodynamic therapy in combination with different drugs. This new system overcomes the limitations of 2D monolayer culture and is capable of testing effectively the capacities of photodynamic therapy in 3D microenvironments with the possibility of real-time monitoring of treatment outcomes.
Evaluation of photodynamic therapy efficiency using an in vitro three-dimensional microfluidic breast cancer tissue model
Hongjun Wang
Added on: 07-14-2021
Imaging approach to study cancer-activated fibroblasts
November 2014
Université Libre de Bruxelles, Brussels, Belgium
To study the activation of fibroblasts during cancerous processes, a multicellular model is used to combine different human breast cancer cell lines with human fibroblasts. By monitoring with infrared imaging, it was possible to see clear differences in the chemical composition of cancer-stimulated fibroblasts, and this was reproducible with stimulation of different breast cancer cell lines. Finally, these changes can be related to secreted factors. This study demonstrates the value of the use of infrared imaging techniques to study microenvironment of breast tumors.
A FTIR imaging characterization of fibroblasts stimulated by various breast cancer cell lines
Erik Goormaghtigh, Saroj Kumar
Added on: 07-30-2021
Characterization of immunosuppressive features in cervical cancer patients' tumors
October 2014
VU University Medical Center, Amsterdam, Netherlands
Cervical cancer is the fourth leading cause of cancer-related death among women worldwide and is caused by sexually transmitted human papillomavirus. Cervical cancer tumor cells are able to escape the immune system by provoking an immunosuppressive state of their microenvironment. In the present study, the researchers studied immune-cell subsets present in tumors from patients by flow cytometry and characterized the profiles of cytokines released by the cells. The data reveals that the immunosuppressive microenvironment in patients with cervical cancer is due to the accumulation of immunosuppressive immune effector cells and elevated levels of cytokine IL10. This study should inform the future development of immunotherapeutic interventions aimed at breaking microenvironmental immune suppression in cervical cancer.
High and interrelated rates of PD-L1þCD14þ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer
Tanja D. de Gruijl
Added on: 09-14-2021
Fluorescence-based assay to study cell proliferation
October 2014
Kyoto University, Kyoto, Japan
An assay is established to have continuous monitoring of cell proliferation of human breast cancer cells through Kaede protein fluorescence. With this technique, the study finds that interleukin-6 has a positive effect on cell proliferation and that it can promote cell proliferation of other cancer cells through paracrine mechanisms. The results show that this method can open new opportunities to study cell proliferation mechanisms of cancer cells.
An optical labeling-based proliferation assay system reveals the paracrine effect of interleukin-6 in breast cancer
Junji Itou
Junji Itou et al. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2015 [898]
EURL ECVAM [899]
Added on: 08-01-2021
In vitro blockade of specific markers to restore NK cell function to fight pancreatic cancer
October 2014
The first Affiliated Hospital of Nanjing Medical University, Nanjing, China
Anti-tumor effect of NK cells decreases during pancreatic cancer progression. In the present study, the researchers aimed at understanding better the regulatory pathways by which NK cells facilitate tumor immune escape. NK cells were isolated from a healthy donor and co-cultured with normal human pancreatic cells and human pancreatic cancer cells. NK cell function was determined by a flow cytometric analysis and bioassay absorption of secreted cytokines. Further, the expression levels of different markers of NK cells functional stages were assessed. The results showed that NK cells function was significantly downregulated following exposure to pancreatic cancer cells compared to normal pancreatic cells, yet blockade of the dysfunctional markers using specific drugs restored NK function. The results should be exploited to develop immunotherapy.
Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction
Yi Zhu, Yi Miao
Added on: 09-14-2021
Mathematical computation of drug targeting model
October 2014
Federal University of Juiz de Fora, Juiz de Fora, Brazil
A mathematical model is used to simulate the effects of the use of the drug Lapatinib in cancer stem cells. The model is a combination of a breast tumor growth model together with a pharmacokinetic model. The obtained results are satisfactory when compared with experimental data, which makes this a potentially useful method to understand drug mechanisms against tumor growth.
Pharmacokinetics simulation of breast cancer
Daniela S Carvalho
Added on: 07-15-2021
Mathematical model of cancer antigen binding
October 2014
National Institutes of Health, Bethesda, USA(1)
Pusan National University, Busan, South Korea(2)
Pusan National University, Busan, South Korea(2)
Immunotoxins and antibody-drug conjugates are designed to bind to specific target antigens on tumor cells and kill these cells. Most cancer-specific antigens are shed from the cell surface without clear knowledge on how this process can affect the delivery efficiency of antibody-drug conjugates and immunotoxins.
In this study, the researchers used a mathematical model to reproduce the kinetic events happening in the blood flow, extracellular space and tumors. The model shows that shedding can reduce, as well as enhance, antitumor activity depending on the number of antigen molecules on the cell surface. It raises the possibility of a new mechanism by which receptor shedding can regulate signaling in normal tissues.
Effect of antigen shedding on targeted delivery of immunotoxins in solid tumors from a mathematical model
Byungkook Lee(1), Youngshang Pak(2)
Added on: 07-27-2021
Vitamin D compounds modulate breast cancer stem cells
October 2014
The State University of New Jersey, Piscataway, USA
Breast cancer stem cells are thought to have a critical role in the development and progression of cancer due to their tumor-initiating and drug resistance capabilities. A vitamin D compound was described to inhibit the transition from ductal carcinoma in situ to invasive ductal carcinoma in breast carcinogenesis. Here, a human breast cancer cell line and a breast epithelial cell line were used to elucidate the influence of vitamin D compounds on breast cancer stem cells. The results show that these compounds could reduce the subpopulation of breast cancer stem cells in treated human breast cancer cells. Moreover, they also induced non-cancerous cell behaviour when treating the same cells to form mammospheres and the mammosphere forming sphere was significantly reduced. Also, these compounds could inhibit the expression of certain markers related to stem cell-like phenotypes. Overall, the researchers demonstrate that vitamin D compounds could modulate breast cancer stem cell subpopulations and potentially hinder breast cancer progression.
Vitamin D compounds reduce mammosphere formation and decrease expression of putative stem cell markers in breast cancer
Nanjoo Suh
Joseph Wahler et al. The Journal of Steroid Biochemistry and Molecular Biology 2015 [906]
EURL ECVAM [907]
Added on: 10-30-2021
Assessing immune genes modifications in colorectal cancer patients
2014
St. George’s Hospital, London, United Kingdom
Patients with colorectal cancer (CRC) experience decreased immune function directly due to the development of the disease. In the present study, the researchers assessed the expression level of immune function genes. The researchers directly measured the expression level of those genes in CRC patients cells and also checked the epigenetic modification of these genes. Survival analysis of these patients was also performed to correlate survival rate with the gene expression and epigenetic modifications. The study shows specific alterations that may offer novel immunomodulatory approaches in the management of CRC.
Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer and their prognostic significance
D. Kumar
Added on: 07-27-2021
Proteomic analysis of breast cancer-associated fibroblasts
2014
University of Vienna, Vienna, Austria
Breast cancer is the most prevalent form of cancer in women. Among all the actors involved in cancer progression, cancer-associated fibroblasts have been described to have a pivotal role. However, this type of cells has not yet been properly characterized. Here, patients' samples from different areas of the tumor and its surroundings were used to perform a proteomic analysis and subsequently compared to reference profiles from activated and non-activated primary human mammary fibroblasts and a human carcinoma cell line. The results showed that, within the tumor, there is a prevalence of cancer cell-related proteins, while in distant areas there is a predominance of fibroblast-related proteins. Furthermore, several proteins related to fibroblast wound healing activity were found in all tissue samples, contrary to inflammatory-related proteins. Overall, the authors of this study establish a proteomic profile of cancer-associated fibroblasts present in different areas of the cancerous wound, which could be used to better understand this cell type and develop new therapeutical strategies based on its modulation.
Proteome profiling of breast cancer biopsies reveals a wound healing signature of cancer-associated fibroblasts
Christopher Gerner
Added on: 10-21-2021
Ex vivo effects of green tea compound on cancer patients immune cells
2014
Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
Green tea contains polyphenols, particularly catechins, the most abundant of which is Epigallocatechin-3-gallate (EGCG) which has been reported to exert in vitro antitumor effects in various types of cancers. In the present study, the researchers investigated the effect of the EGCG on the proliferation and capacity to secrete cytokines of immune cells isolated from cancer patients. EGCG significantly suppressed the proliferation of immune cells and cytokine secretion. Such observations may contradict the use of EGCG in cancer immunotherapy, and suggests that further studies on its use as an immunomodulatory agent in autoimmune diseases and tissue transplantation are needed.
Analysis of the effect of the active compound of green tea (EGCG) on the proliferation of peripheral blood mononuclear cells
Farid Saleh
Added on: 09-14-2021
Improving breast cancer subtypes diagnosis through bioinformatic analysis
2014
Northwestern University, Evanston, USA
In the present study, the researchers used computational techniques to analyze gene expression patterns from breast cancer patients data which are publically available from The Cancer Genome Atlas (TCGA). Novel signatures associated with transcription factor STAT3 (Signal transducer and activator of transcription 3) were identified and were shown to be specific for basal-like breast cancer and not seen in other subtypes such as luminal A or luminal B cancers. Because STAT3 is known to be important for basal-like breast cancer malignancy, elucidating its most highly affected downstream targets is of great importance to cancer diagnosis and therapy.
Bioinformatic analysis reveals a pattern of STAT3-associated gene expression specific to basal-like breast cancers in human tumors
Curt M. Horvath
Added on: 07-26-2021
miRNA-29 promotes invasive behavior in human breast cancer cells
2014
University of Alabama at Birmingham, Birmingham, USA
N-Myc Interactor, whose expression is affected in advanced stages of breast cancer, is involved in maintaining epithelial phenotype. Its downregulation can induce a metastatic phenotype of cancer cells in breast tumors. Thus, it is potentially involved in several critical processes in breast cancer development and metastasis. Here, 2D and 3D culture models with human breast cancer cell lines and patients' samples were used to investigate miRNAs that can potentially regulate N-Myc Interactor's expression and promote metastatic behaviour in cancer cells. The results show that miR-29 is more expressed in cancer cells that underwent the epithelial-to-mesenchymal transition. Moreover, in 2D and 3D cultures, miR-29 promoted a mesenchymal cell-like morphology. Furthermore, the modulation of miR-29 in different cell lines with high and low expression of N-Myc Interactor resulted in a negative correlation with N-Myc Interactor expression. Additionally, this was confirmed in samples from patients. Finally, the mechanism responsible for the upregulation of miR-29 expression in the absence of the N-Myc Interactor was elucidated. Overall, the researchers demonstrate a new potential therapeutical target that develops a positive regulatory loop that enhances miR-29 expression through the downregulation of the N-Myc Interactor, which promotes epithelial-to-mesenchymal transition and leads to tumor invasive behavior.
microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer
Rajeev S Samant
Added on: 10-25-2021
New biomarkers for rare type of lymphoma identified in patients material
2014
McGill University Health Centre, Montréal, Canada
Cutaneous T-cell Lymphoma (CTCL) is a rare type of cancer in which pathogenesis remains only partially understood. Identification of novel diagnostic markers and future therapeutic targets are essential. In the present study, the researchers have tested the expression of cancer-testis genes (CT) in a cohort of CTCL patients, normal skin samples, skin from benign inflammatory dermatoses and patient-derived CTCL cells. The study shows that a number of CT genes are specifically expressed in CTCL patients and can be used as biomarkers or novel targets for immunotherapy.
Ectopic expression of cancer testis antigens in cutaneous T-cell lymphoma (CTCL) patients
Denis Sasseville, Ivan V. Litvinov
Added on: 09-14-2021
Smad3 shows anti-tumor activity in breast cancer cells
2014
Northwestern University Feinberg School of Medicine, Chicago, USA
Cyclin D1/CDK4 activity is upregulated in 50% of breast cancers and is involved in the inhibition of Smad3. However, it is still unclear whether how CDK4 inhibition can modulate Smad3-dependent cell/colony growth and apoptosis in breast cancer cells. Here, human breast cancer cells overexpressing cyclin D1 were used to investigate if CDK4 inhibitor, doxorubicin, modified Smad3 or a combination therapy could impact cancerous activity in these cells. The results showed that the combination therapy or the overexpression of Smad3 resistance to CDK4 phosphorylation lead to a decrease in colony formation and an inhibition of various cancer cell-related features. Moreover, the overexpression of the mutated Smad3 combined with doxorubicin treatment caused the greatest increase in the expression of apoptotic-related proteins. Overall, the researchers suggest an important Smad3 tumor suppression activity that can be synergistically complemented with doxorubicin treatment in cyclin D1-overexpressing cancer cells and point to CDK4 as a potential novel target in cancer therapy.
CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin
Jacqueline S Jeruss
Added on: 11-01-2021
In silico analysis of sequences of prostate cancer marker
2014
University of Beira Interior, Covilha, Portugal
The six transmembrane epithelial antigen of the prostate 1 (STEAP1) is present almost exclusively in prostatic cells; although it was shown to be overexpressed in prostate cancer, its function is not clear. In the present study, the researchers conducted an extensive in silico analysis of STEAP1 and related gene STEAP1B, and evaluate the in vitro STEAP1 and STEAP1B expression in human prostate cell lines. In addition, the putative post-transcriptional and post-translational modifications are evaluated through STEAP1 mRNA and protein stability, supplemented by a post-translational in silico analysis. The data indicate that STEAP1B2 is overexpressed specifically in neoplastic cells, and post-translational modifications may be involved in the regulation of STEAP1 expression in prostate cells.
Expression of STEAP1 and STEAP1B in prostate cell lines, and the putative regulation of STEAP1 by post-transcriptional and post-translational mechanisms
Cláudio J Maia
Added on: 09-18-2021
Mathematical modeling of signaling network response
2014
University of Michigan, Ann Arbor, USA
Modelling signalling networks dynamics is still a challenging task. In this study, a mathematical model is used to predict the dynamics of signalling networks response under unseen perturbations. This algorithm is based on three steps and is validated against simulation and experimental data. Additionally, when compared with other available methods, the computational time is reduced by magnitudes, what potentially will allow the genome-wide modelling of signalling pathways in practical times.
Predicting dynamic signaling network response under unseen perturbations
Yuanfang Guan
Added on: 07-18-2021
3D organotypic cultures with automated image analysis for drug screening
2014
University of Turku, Turku, Finland
The study presents the validation of a high-content workflow based on coupling 3D culture models with automated image analysis. This platform is used to quantify actin-target treatment-induced morphological changes of several human prostate and breast cancer lines embedded in 3D extracellular matrix structures. Through this approach, it was possible to identify three drugs that attenuate invasive dynamics and study their signalling mechanisms, showing that this model can be a very powerful tool for large-scale drug screening/discovery and target validation.
Quantification of dynamic morphological drug responses in 3D organotypic cell cultures by automated image analysis
Matthias Nees
Added on: 07-20-2021
Microfluidic device to model heterogeneous tumours
2014
Korea University, Seoul, South Korea
There is a lack of knowledge on the effect of tumour subpopulations heterogeneity in tumour progression and invasion. Current in vitro models have severe limitations that impede the correct modelling of intratumour heterogeneity in vitro. Here, a novel microfluidic system is developed to study two different human breast cancer cell lines co-cultured in extracellular matrix scaffolds that mimic the tumour microenvironment. The results showed that intratumour heterogeneity increases cancer cell invasive behaviour depending on the neighbouring extracellular matrices. Moreover, this system allowed to elucidate the cellular dynamics that initiate and drive cell invasion through the interplay between different cancer cell subpopulations and the influence of cellular heterogeneity in enhancing the metastatic potential. Overall, the researchers develop a new microfluidic system that allows studying metastasis mechanisms in a relevant in vitro system that can replicate in vivo features of heterogeneous tumours.
Intratumoral phenotypic heterogeneity as an encourager of cancer invasion
Seok Chung
Added on: 10-19-2021
New potential target for immunotherapy discovered from lung cancer patients' tissues
2014
University of Florida, Gainesville, USA
Initiation and progression of lung cancer mainly relies on the tumor microenvironment. Interaction between cancer cells and part of the immune system has been shown to facilitate cancer cell invasion and metastasis, although the molecular mechanisms at play are poorly understood. In the present study, the researchers aimed at analysing if the presence of one particular receptor called Triggering receptor expressed on myeloid cells 1 (TREM-1) could be a predictor of lung cancer patients prognosis. Using tumor tissue from patients, the researchers showed an increased expression of TREM-1. Immunohistochemistry and immunofluorescence on the patients' tissues showed that the expression of TREM-1 was selectively seen in a particular type of macrophage. The data was confirmed in vitro when co-culturing macrophages with cancer cells. The study proposes that TREM-1 might be a novel target for tumor immunomodulation.
TREM-1 is induced in tumor associated macrophages by Cyclo-Oxygenase pathway in human Non-Small Cell Lung Cancer
Ruxana T. Sadikot
Added on: 09-17-2021
Chamber to model monocyte endothelial transmigration
2014
Chonnam National University, Gwangju, South Korea
A chamber-based migration assay id developed that combines the use of human umbilical cord vein endothelial cells, alginate gels and polycarbonate membranes. It is used to study the endothelial transmigration capacity of modified monocytes to a region of interest filled with chemo-attractants. Monocytes were able to migrate through the different layers of the chambers, showing that they are attracted by human breast cancer cells and that the model can be efficiently used to study the migration capabilities of different cell types.
Monocyte-based microrobot with chemotactic motility for tumor theragnosis
Sukho Park, Jong-Oh Park
Added on: 07-23-2021
Computational deconvolution of tumor sequencing data
2014
University of California, Irvine, USA
Two types of sequencing information are combined to improve the identifiability of reads associated with certain tumour cells or subclonal types. This method, which is available in a Python package named PyLOH, is able to outperform existing methods when used in both simulated data and in real breast tumour datasets. Therefore, it can be a useful tool to determine the subclassification of sequencing reads in mixed tumour cell populations.
Deconvolving tumor purity and ploidy by integrating copy number alterations and loss of heterozygosity
Xiaohui Xie
Added on: 07-28-2021
Mechanisms of estrogen-induced cell proliferation
2014
University of New Mexico Health Sciences Center, Albuquerque, USA
Estrogen is a key hormone for the normal development of mammary glands that stimulates epithelial proliferation. This activity of estrogen is thought to act through estrogen receptor alpha, which has been shown to be involved in estrogen-mediated proliferation both in normal and tumorigenic conditions. Recent findings also proposed G protein-coupled estrogen receptor to play a role in proliferation modulation in breast cancer cells, although the signalling mechanisms remain unclear. Here, human non-tumorigenic breast epithelial cells and human ex vivo breast tissue organotypic culture were used to investigate the mechanisms that link the G protein-coupled estrogen receptor to proliferation. The results showed that the activation of the receptor increased the proliferative status in both models. Moreover, through selective inhibition of signalling pathways, it was possible to identify several secondary messengers involved in the signalling cascade. Further confirmation of the involvement of the G protein-coupled estrogen receptor was obtained by inhibiting the induction of proliferation by selectively inhibiting or knocking down G protein-coupled estrogen receptor. In this study, the researchers partially elucidate the involvement of the G protein-coupled estrogen receptor and the mechanisms underlying this in normal and tumorigenic tissue in two different human models, opening the door to new potential therapeutic targets for breast cancer treatments.
GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast
Helen J Hathaway
Added on: 10-11-2021
Fibroblasts facilitate permeability of an in vitro blood-brain barrier
2014
Yonsei University College of Medicine, Seoul, South Korea
To study the importance of fibroblasts in brain metastasis, several assays in several models are used. Also, two new 3D models are developed with human cells to study the permeability of a multicellular in vitro blood-brain barrier, transmigration and breast cancer cell colony formation. These new devices provide mechanistic insights into cancer-associated fibroblasts in breast cancer brain metastasis.
Cancer-associated fibroblast promote transmigration through endothelial brain cells in three-dimensional in vitro models
Nam Hoon Cho
Added on: 07-16-2021
Mathemathical models for metastasis prediction
2014
Ondokuz Mayis University School of Medicine, Samsun, Turkey
The study presents the building of a new nomogram for predicting non-sentinel lymph node metastasis in sentinel lymph node patients with invasive human breast cancer to try to overcome the need of performing axillary lymph node dissections. The nomogram was built taking into account several independent predictive factors and, together with other selected models, they showed excellent discrimination capacities. After testing several models in 237 patients, the researchers found several properties of breast tumours that can be predictive factors. Here, a new nomogram is presented that could be used to predict the likelihood of non-sentinel lymph node metastasis.
A breast cancer nomogram for prediction of non-sentinel node metastasis - validation of fourteen existing models
Bekir Kuru
Added on: 07-30-2021
New assay to elucidate cancer cell migration mechanisms
2014
McGill University, Montreal, Canada
A cost-effective assay is developed to study the role of extracellular matrix proteins in cancer cell migration. The assay allows the visualisation of different migration patterns depending on the extracellular matrix proteins used. Different human cancer cell lines are used separately in 2D monolayer culture to validate this assay. The results show that collagen is a promoter of cell migration in all lines without affecting proliferation. This new assay shows to be a promising and approachable assay to study cell migration "in vitro".
Ring cell migration assay identifies distinct effects of extracellular matrix proteins on cancer cell migration
Josephine Nalbantoglu
Added on: 07-27-2021
Cancer cell-induced matrix remodeling in 3D culture
2014
FOM Institute AMOLF, Amsterdam, Netherlands
Development of a new assay to study cancer cell migration in a hydrogel-based 3D model is presented. In the presence of human breast cancer cells, there is a reorganisation of the fibres of the extracellular matrix done by "leader" cells, which subsets the matrix in different subregions. Afterwards, other cells following a more randomised migratory profile invade these subsetted regions. This platform supports the study of micromechanical propertiesof cell cancer migration.
Effects of migrating cell-induced matrix reorganization on 3D cancer cell migration
Nicholas Agung Kurniawan
Added on: 07-27-2021
Human cancer cell lines used to assess if CD22 is a valid marker
2014
UT Southwestern Medical Center, Dallas, USA
Lung cancer is the leading cause of cancer death worldwide. A major goal in this field is to identify novel targets to treat tumors. Some reports indicated that transmembrane protein CD22 was expressed on lung cancer cells and might serve as a new target for therapy. In the present study, the researchers used a combination of flow cytometry and Western blot analyses with a variety of CD22 monoclonal antibodies and could not detect surface or intracellular expression of CD22 protein in a panel of human lung cancer cell lines. In addition, the proliferation of these cancer cell lines in vitro was not affected using CD22 antibodies or a highly potent anti-CD22 immunotoxin. The study concludes by asking for more investigation on the reality of CD22 as a specific marker of cancer cells before any development of therapy is made.
A reevaluation of CD22 expression in human lung cancer
Ellen S. Vitetta
Added on: 09-13-2021
Immune response analysis using cancer patients' cells during chemotherapy
2014
Attikon University Hospital, Athens, Greece
Recently, immune evasion by malignant cells has been identified as one of the crucial hallmarks of cancer development. Regulatory T-cells (Tregs) are the most extensively studied suppressive cells and increasing evidence suggests that cancer progression correlates with an increase in Treg activity. In the present study, the researchers aimed at investigating the effect of chemotherapy on the number and functionality of peripheral regulatory and effector T-cells in cancer patients. Regulatory and effector T-cells were purified from cancer patients and cultured in vitro to assess proliferative capacity before and during various chemotherapeutic regimens. The obtained results showed a clear shift in favour of regulatory T-cells during chemotherapy. There was a relative increase of regulatory to effector T-cells and suppressive activity was augmented. Differences were noted comparing different chemotherapy approaches, underlining the importance to better understand the effect of chemotherapeutics on the immune response to select the most advantageous drug, particularly if the drug is to be used in combination with immunotherapeutics.
The effect of metronomic versus standard chemotherapy on the regulatory to effector T-cell equilibrium in cancer patients
Anna Koumarianou
Added on: 09-14-2021
Improved protocol to expand patients cells ex vivo for cancer immunotherapy
2014
Uppsala University, Uppsala, Sweden
Adoptive T-cell therapy of cancer is a treatment strategy where T cells are isolated, activated, in some cases engineered, and expanded ex vivo before being reinfused to the patient. Unfortunately, T cells expanded using the commonly used “rapid expansion protocol” (REP) are sensitive to the harsh tumor microenvironment and are often shortlived after reinfusion. In the present study, the researchers demonstrate that an alternative "allosensitized allogeneic lymphocytes expansion protocol" (AEP) allow for obtaining T cells with better survival and cytotoxic efficacy under oxidative stress and immunosuppressive environment, as well as a superior proliferative response during tumor cell killing compared to the REP protocol. These results show a robust ex vivo method to expand T cells with improved quality for adoptive cancer immunotherapy. T cells were isolated from donors' peripheral blood and expanded ex vivo. Assays for cytotoxicity were done in vitro using established human cell lines.
Allogeneic lymphocyte-licensed DCs expand T cells with improved antitumor activity and resistance to oxidative stress and immunosuppressive factors
Magnus Essand
Added on: 07-28-2021
3D multicellular microfluidic model to study metastases mechanisms
December 2013
IRCCS Istituto Ortopedico Galeazzi, Milano, Italy(1)
Massachusetts Institute of Technology, Cambridge, USA(2)
Massachusetts Institute of Technology, Cambridge, USA(2)
Cancer metastases are complex phenomena that begin with the extravasation of circulating tumor cells. Additionally, certain tumor cells seem to specifically target certain organs, thus complex in vitro models are needed to elucidate the mechanisms underlying this process. Here, a 3D microfluidic model is used to investigate the interactions between human endothelial cells, osteo-cells differentiated from bone marrow-derived mesenchymal stem cells and human adenocarcinoma cancer cells and to study the transendothelial migration of metastatic cells into a bone-like environment. The presence of osteo-cells induced an increase in extravasation and migration distance of cancer cells, which resulted in the formation of micrometastases. Furthermore, a breast cancer cell receptor and a bone-secreted chemokine were identified to play a major role in this process. Overall, the researchers propose a complex multicellular 3D microfluidic model that can be used to decipher the metastatic mechanisms and the main factors involved in a human context.
A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone
Matteo Moretti(1), Roger D Kamm(2)
Added on: 10-06-2021
Culture platform to control cancer cell growth
November 2013
Chinese Academy of Sciences, Shenyang, China(1)
City University of Hong Kong, Hong Kong, Hong Kong SAR of China(2)
City University of Hong Kong, Hong Kong, Hong Kong SAR of China(2)
A new culture platform is developed to allow for specific patterns during cancer cell growth. Using optically-induced electrokinetics, it is possible to imprint specific patterns in glass substrates topped with hydrogels. Additionally, this study shows that, effectively, cultured human breast cancer cells grow in the specific patterns designed with this technique. This can be useful to study the effects of cell geometry during cell expansion.
Extracellular-controlled breast cancer cell formation and growth using non-UV patterned hydrogels via optically-induced electrokinetics
Lianqing Liu(1), Wen J Li(2)
Added on: 07-29-2021
Lapatinib disrupts proliferation of cancer stem cells
November 2013
University Hospital of South Manchester NHS Foundation trust, Manchester, United Kingdom(1)
University of Manchester, Manchester, United Kingdom(2)
University of Manchester, Manchester, United Kingdom(2)
A combination of invasive and non-invasive interventions in patients of ductal carcinoma in situ has reduced recurrence rates, but not mortality. This is thought to be because of the survival of cancer stem cells resistant to radiotherapy. HER2 is overexpressed in 20% of ductal carcinoma in situ and highly active in cancer stem cells. Thus, Lapitinib's effects on ductal carcinoma in situ cancer stem cells were investigated. Human ductal carcinoma in situ cell lines and samples from patients were used to perform mammosphere assays and to differentiate in 3D culture to investigate the effects of Lapatinib in cancer stem cells and non-cancer stem cells. The results showed a decrease in mammosphere formation and cancer stem cell proliferation without affecting cancer stem cell self-renewal, regardless of HER2 expression. However, Lapatinib only affected the proliferation of HER2+ cells in the differentiation model. Overall, the researchers elucidate the effects of Lapatinib on ductal carcinoma in situ cancer stem cells and suggest its potential use in high-risk patients to reduce the tumour progression to metastasis.
Lapatinib inhibits stem/progenitor proliferation in preclinical in vitro models of ductal carcinoma in situ (DCIS)
Nigel Bundred(1), Gillian Farnie(2)
Added on: 10-11-2021
A DEP-array allows direct measurement of immune lysis
2013
Regina Elena National Cancer Institute, Immunology Laboratory, Rome, Italy
DEP arrays - chip platforms based on dielectrophoresis (DEP) - have the advantage that they allow direct measurement of cell lysis by identifying individual cells and capturing them in DEP "cages". "Cages" and their contents can be moved within the chip to any location on its surface. In this way, controlled and forced interactions between cells can be induced and infected cells and tumors can be detected. Here, DEP-based manipulations of human single CTL (Cytotoxic Lymphocyte) and NK (Natural Killer) cells as well as controlled and forced interactions were performed to understand and control lytic interactions. Specific lysis could be measured in real time and target cells with different susceptibility to immunolysis were identified. Applications are foreseeable in human immunology, including antiviral surveillance and tumor immunotherapy.
Lysis-on-Chip of single target cells following forced interaction with CTLs or NK cells on a dielectrophoresis-based array
Patrizio Giacomini
Added on: 05-27-2020
Arrhythmia model using human induced pluripotent stem cells for drug safety testing
2013
SAIC-Frederick National Laboratory for Cancer Research, Frederick, USA
Cardiovascular liabilities of new chemical entities continue to be a significant source of attrition across the entire drug discovery and development process. Among the most common drug-induced cardiovascular findings encountered are disturbances in the electrical activity of the myocardium. Hence, novel screening models that are capable of incrementally improving the ability to assess a drug’s arrhythmogenic potential are needed. Human iPSC-derived cardiomyocytes (hiPS-CMs) have been shown to respond to known selective modulators similarly to a human heart. In the present study, the researchers assessed changes in the beat rhythm and rate of a confluent monolayer of hiPS-CMs by 118 compounds. This assay showed increased performance over existing preclinical tools in predicting clinical arrhythmia. In conclusion, hiPS-CMs are a relevant cell system to improve evaluating cardiac safety liabilities of drug candidates.
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model
Liang Guo
Added on: 11-29-2021
Targeting breast cancer stem cells with ellipticine
2013
National Institute of Pathology, New Delhi, India
Breast cancer stem cells are surging as a potential target to disrupt cancer progression and avoid further relapses. Here, the effects of ellipticine on ALDH1A1-expressing human breast cancer stem cells are studied both in in vitro and in silico setups. The results show that at concentrations of 3mM it was able to significantly decrease the ALDH1A1+ cancer stem cells in two different human breast cancer cell lines. Contrary to paclitaxel, ellipticine also reduced mammosphere formation but, when both agents were combined, there was an enormous drop of ALDH1A1+ cancer stem cells. The in silico model revealed that several residues of ALDH1A1 were potentially interacting with ellipticine, confirming the potential interactions of the drug with this protein. In this study, the researchers demonstrate that ellipticine can disrupt the proliferation abilities of ALDH1A1+ breast cancer stem cells and can be combined with cytotoxic therapeutical agents to efficiently target them.
Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells—an in vitro and in silico study
Sunita Saxena
Added on: 10-14-2021
Chips simulate the tumor microenvironment
2013
Massachusetts Institute of Technology, Cambridge, USA
Cancer spheroid dispersion assays are used to mimic the epithelial-to-mesenchymal transition (EMT) that occurs in the early stages of cancer metastasis. Cancer spheroids can be seeded in 3D hydrogels on chips and cultivated together with secondary cell types (such as endothelial cells) to more accurately mimic the tumor microenvironment. The migration rates of cancer cells and other details of the process can be closely monitored in real-time to gain insight into the development of metastases, which are responsible for 90% of cancer-related deaths.
A 3D system of adenocarcinoma cell spheroids can be used for drug screening.
Screening therapeutic EMT blocking agents in a three-dimensional microenvironment
Roger D. Kamm
Added on: 07-09-2020
Tomographic technique applied to breast cancer diagnosis
2013
Universidade de São Paulo, Ribeirão Preto, Brazil
A computational study to test whether topographic Rayleigh to Compton scattering ratio can be used in human breast cancer diagnosis. Several parameters are studied to evaluate the technique, showing that the contrast of the images depends on how they are adjusted. Also, the statistical noise was important, but without concerning influence in the final quality of the images. Overall, the results show that this technique could, effectively, be used s a complementary tool in breast cancer diagnostics.
Rayleigh to Compton ratio scatter tomography applied to breast cancer diagnosis: a preliminary computational study
Marcelo Antoniassi
Added on: 07-30-2021
A versatile assay for monitoring in vivo-like transendothelial migration of neutrophils
2012
Korea University, School of Mechanical Engineering, Seoul, South Korea
Leukocyte transendothelial migration (TEM) is a multi-step process in the inflammatory response that plays critical roles in the defence against invading pathogens (triggered by bacteria and its degradation products entering the body by wounds) and the development of diverse immune disorders, as well as abnormal collagen stiffness, including angiogenesis and cancer-cell metastasis.
This method allows for establishing in vivo-like inflammatory models in a microfluidic device and quantitatively measuring the three-dimensional transendothelial migration of neutrophils during the inflammatory process, induced by various inflammatory stimuli. It can enable the anaylsis of the interplay among various immune cells, different types of endothelial cells and other blood cells. This device can be used for phenotype-based, high-throughput drug screening.
A versatile assay for monitoring in vivo-like transendothelial migration of neutrophils
Seok Chung
Added on: 05-29-2020
Olaparib to treat non-BRCA breast cancer
2012
Kawasaki Medical School, Kurashiki, Japan
BRCA is a risk genetic marker of developing familial breast cancer. There are some therapeutic agents that have been shown to be effective against this type of cancer, like olaparib. However, there is little information about their anti-tumour activity in non-BRCA sporadic breast cancer. Here, several human cell lines derived from patients with sporadic breast cancer were used to test the effects of olaparib, alone or in combination with other chemotherapeutic agents, on different cancer-related features in these cells. The results show that olaparib inhibited the growth of different types of breast cancer cells through cell cycle arrest and induction of apoptosis but was ineffective in two HER+ breast cancer cell lines. However, in all cell lines, there was a significant decrease in the proportion of cancer stem cells. Olaparib also increased the expression of p-EKR, and its inhibition could counteract the effect of olaparib. Only one of the chemotherapeutic agents tested together with olaparib seemed to have additive anti-tumour activity and it further increased the observed effects of olaparib alone. In this study, the researchers demonstrate the anti-tumour activity of olaparib in non-BRCA human breast cancer cells and partially elucidate its mechanisms of action. They also describe a potential combinatory therapeutic strategy that could be used to treat non-BRCA sporadic breast cancer.
Antitumor and anticancer stem cell activity of a poly ADP-ribose polymerase inhibitor olaparib in breast cancer cells
Junichi Kurebayashi
Added on: 10-19-2021
Cell transformation assay to detect carcinogenicity
Regulatory accepted 2012
European Union Reference Laboratory for Alternatives to Animal Testing, Ispra, Italy
The in vitro CTA using Bhas 42 cell line is aimed at detecting the carcinogenic potential of chemicals. The assay is based on the change of the phenotypic features of cells undergoing the first steps of the conversion from normal cells to neoplastic-like cell foci with oncogenic properties. The current protocols consist of two assay components, the initiation assay and the promotion assay to detect the tumour-initiating and tumour-promoting activity of chemicals, respectively.
Validated and regulatory approved under TM2012-06 (EU) by EURL ECVAM (TSAR list), OECD Guidance Document 231.
Cell transformation assay based on the bhas 42 cell line
EURL ECVAM
Added on: 07-03-2020
3D model to study epithelium-stroma interplay in pulmonary diseases
2011
Tufts University School of Medicine, Boston, USA
Alterations in the interplay between epithelial and stromal tissue have been shown to be critical in several human pathologies, also in pulmonary diseases such as asthma, fibrosis or cancer. Here, a 3D in vitro model of the human airway was built using a type-I collagen matrix populated with healthy or cancer-associated human lung fibroblasts and normal human bronchial epithelial cells to study epithelial-mesenchymal interactions. The results showed that the generated culture had a well-differentiated pseudo-stratified multilayer structure recapitulating the in vivo organization. Co-culture with normal fibroblasts induced the formation of typical respiratory surface epithelium, while cancer-associated fibroblasts caused epithelial cells to acquire an invasive phenotype. Moreover, the data suggest that this erroneous behaviour might be led by biomechanical signals associated with the extracellular matrix. Furthermore, paracrine signalling from cancer-associated fibroblasts induced epithelial cells to express genes associated with several pathological processes. Overall, the researchers demonstrate that this newly developed model can be used to study the pathological interactions between epithelium and cancer-associated fibroblasts that lead to dysfunction of normal epithelial cells.
The effect of stromal components on the modulation of the phenotype of human bronchial epithelial cells in 3D culture
Carlos Sonnenschein
Added on: 11-25-2021
Carcinogenicity assay
Regulatory accepted 2004
European Union Reference Laboratory for Alternatives to Animal Testing, Ispra, Italy
The In-vitro-CTA using the BALB/c 3T3 cell line is aimed at detecting the carcinogenic potential of chemicals. The assay is based on the phenotype change of cells undergoing the first steps of the conversion from normal cells to cell foci with oncogenic properties.
In vitro CTAs such as the BALB/c 3T3 CTA have been shown to recapitulate a multistage process that closely models some stages of in vivo carcinogenesis.
Validated under TM2004-07 (EU) by EURL ECVAM (TSAR list), regulatory acceptance is ongoing.
In vitro BALB/c 3T3 Cell Transformation Assay
EURL ECVAM
Added on: 07-03-2020
(Multi-)organ-on-chip technologies for the development of personalized (disease) models
CompanyReact4Life, Genova, Italy
To improve cancer research and drug development, the company React4Life has specialized in the development of organ-on-chip technologies (MIVO). The MIVO platforms are compatible with various tissue samples and enable the cultivation of three-dimensional personalized models in a controlled microenvironment. The single organ platforms are used to research specific organ functions and to investigate the effects of drugs on specific organs, such as the influence of cardiac drugs on the pumping power of the heart muscle tissue. The multi-organ platforms simulate the interaction between different organs and enable research into disease- or drug-induced interactions, such as the consequences of the invasion of malignant cancer cells into other tissues. The (multi-)organ platforms offer an innovative solution for researching specific organ functions and modelling various diseases. The microfluidic models developed with MIVO are therefore suitable for a variety of different studies and can help to improve the safety assessment of drugs and accelerate the development of (personalized) drugs.
MIVO Organ-on-chip
www.react4life.com
Added on: 10-24-2023
3D printed tumors from patient material
CompanyCarcinotech Ltd., Edinburgh, United Kingdom
The Carcino3D™ technology of the company Carcinotech is developed from patient biopsies, whole blood, and immune cells with a heterogeneous population of cells isolated directly from the biopsy and a detailed characterised patient profile with sequencing and mutation data available. These printed patient tumours are available in 96 or 384 well formats with tumour-specific extracellular matrix (ECM) and can also include tumour infiltrating lymphocytes (T cells, B cells, NK cells, etc.) and tumour-associated macrophages. As per request, also vascularised and irradiated tumours for combination therapies can be developed.
Carcino3D™ Technology
info@carcinotech.co.uk
Added on: 01-30-2023
A 3D in vitro model of melanoma
CompanyMatTek Corporation, Ashland, USA
MatTek’s Melanoma model consists of human malignant melanoma cells, normal, human-derived epidermal keratinocytes and normal, human-derived dermal fibroblasts, which have been cultured to form a multilayered, highly differentiated epidermis with melanoma cells at various stages of malignancy. Structurally, the Melanoma model closely parallels the progression of melanoma in vivo, thus providing a valuable tool to study, understand, and develop preventative and therapeutic treatments for one of the most serious cutaneous malignancies. MatTek’s Melanoma tissues have been utilized with a number of target and anti-melanoma drugs. Suitable for studying tumor invasion and anti-melanoma drug screening.
information@mattek.com
Added on: 07-13-2020
AI-assisted (epi-)genetic screening platforms for toxicology and efficacy studies
CompanyToxGenSolutions B.V., Maastricht, Netherlands
The company ToxGenSolutions specializes in identifying drug targets and developing new drugs. The company's goal is to detect severe diseases (such as neurodegenerative diseases, cancer, (auto-)immune deficiencies) at an early stage and stop them in their tracks. Based on (epi)genetic data sets, computer tools identify potential drug candidates. For toxicity and efficacy evaluation, human spheroids are exposed to the active ingredient to be tested and subjected to high-throughput screening. The AI-based methods accelerate previous complex and time-consuming testing procedures. They also open up the possibility of developing personalized medicines. In addition to processes for developing and testing the safety and efficacy of new active ingredients, the company also develops various methodological tools to optimize early diagnostics. Currently, ToxGenSolutions is working to validate a diagnostic tool that will enable preclinical diagnosis of Alzheimer's disease with a focus on differences between men and women.
ToxGenSolutions
erwin.roggen@toxgensolutions.eu
Added on: 11-22-2023
AI-based platform for the development of cancer therapeutics
CompanyBioCopy AG, Basel, Switzerland
The company BioCopy specializes in the development of cancer therapeutics using AI-supported methods. The drug discovery platform enables effective screening for drug candidates that are able to connect the tumor cells with the body’s own immune cells by recognizing specific surface markers. The binding leads to the immune cell specifically killing the cancer cell without damaging the surrounding healthy cells. To engineer the highly complex antibody therapeutics, various technologies are combined in an automated process. The method shows high time and cost savings compared to conventional processes and is able to provide high-quality active ingredients on a large scale for industry. To date, the company has developed three drug development programs in solid tumors (bladder cancer, ovarian cancer, lung cancer) and two in blood cancers (acute myeloid lymphoma). In the future, BioCopy would like to expand the platform for screening drugs against neurological and immunological diseases. In summary, the method can help to accelerate drug development and optimize existing drug therapies.
We revolutionize the development of next-generation cancer drug candidates
info@biocopy.com
Added on: 04-23-2024
AI-powered image analysis platform for early risk assessment of breast cancer patients
CompanyOwkin, Boston, USA
The company Owkin has developed the AI-supported image analysis platform RlapsRisk® BC for an early assessment of the risk of recurrence in breast cancer patients. The method is suitable for adults who have been diagnosed with primary invasive breast cancer (ER+/HER2-). To assess the risk, surgically removed patient tumor tissue samples are examined on digitized slides. Artificial intelligence analyses patterns and characteristics of the tumor and compares them with a clinical data set that includes data from 1,800 breast cancer patients (including 1,480 HER2-/HR+). A machine learning system automatically integrates new insights, meaning the platform is in continuous training to improve the accuracy of its predictions. So far it has been shown that the platform has a cumulative sensitivity of 76% and therefore correctly diagnoses more high-risk patients as positive than the clinical score. After five years, the diagnostic procedure achieved a dynamic specificity of 76%. In summary, the RlapsRisk® BC platform can help doctors better assess the risk of their patients in order to decide on an appropriate form of therapy as early as possible. Furthermore, the researchers hope that the method will provide new insights and an improved understanding of the mechanisms of highly aggressive tumors in the future.
RlapsRisk® BC. Assess the risk of breast cancer relapse.
www.owkin.com
Added on: 01-18-2024
AI-supported development of universal personalized TCR immunotherapies against cancer
CompanyTcelltech GmbH, Mannheim, Germany
Tcelltech GmbH specializes in the development and production of TCR immunotherapy technologies. In collaboration with the German Cancer Research Center (DKFZ), the company has developed the personalized adoptive cell therapy UNIPACT, which is intended to enable universal control of all types of cancer. UNIPACT is based on two different platforms. The AI-based bioinformatics platform selectTCR enables the identification of reactive T cell receptors (TCRs) that recognize and specifically target tumor cells within a few days. Because the TCRs come directly from patients, they do not cause off-target toxicity and can be immediately used to produce modified T cells. SelectTCR's proof-of-concept has been carried out in previous studies in melanoma, colon, pancreatic, lung and brain cancer. The company has developed the high-performance DNA vector platform nanoSMAR to load the patient's own T cells with the selected TCRs. nanoSMAR enables safe and efficient gene expression without damaging cells or activating the immune system. The technology allows long-term gene expression with large genetic capacity. In summary, UNIPACT proves to be a groundbreaking approach that accelerates the development of personalized cancer therapies and can help increase patients' chances of survival and reduce undesirable therapeutic side effects.
Pioneering antigen-agnostic TCR T cell therapies
info@tcelltech.de
Added on: 04-02-2024
AI-supported diagnostics and prognosis platform for assessing the risk of (intestinal) cancer patients
CompanyOwkin, Boston, USA
To classify and assess the risk of colorectal cancer, the company Owkin has developed the AI-supported diagnostic tool MSIntuit® CRC. The method enables digital pre-screening of surgically removed tumor tissue samples for the presence (or absence) of genetic microsatellite instability (MSI). Approximately 15% of the entire colon cancer population has MSI, of which approximately 20% are affected by hereditary Lynch syndrome (HNPCC), which is why MSI is considered a valuable biomarker for the diagnosis of colorectal cancer (CRC) and for predicting the course of the disease. So far it has been shown that the AI predictions have a sensitivity of 95%. MSI pre-screening also plays an important role in determining the treatment decision. Colorectal cancer patients with MSI show better prognoses and do not benefit from chemotherapy in stage II. In addition, the screening platform may also be relevant for other tumor diseases, as therapy with immune checkpoint inhibitors (ICI) is particularly suitable for MSI patients (regardless of the type of cancer). Approved or recommended MSI screening technologies currently used by Owkin include MMR-IHC staining, MSI-PCR testing and next-generation sequencing (NGS). In summary, the MSIntuit® CRC test procedure can help to predict the risk and progression of (intestinal) cancer in order to make an appropriate therapy selection for the patient at an early stage and help to identify familial risks.
MSIntuit® CRC. Optimize MSI testing for colorectal cancer.
www.owkin.com
Added on: 01-25-2024
AI-supported machine learning system to optimize cancer imaging diagnostics
CompanyKeyZell, Sevilla, Spain
To optimize cancer imaging diagnostics, the biotechnology company KeyZell has developed the AI-based Oncology Precision System (O.P.S.) in collaboration with One Technology. O.P.S is a machine learning system trained on 108,948 chest X-ray images from over 30,000 patients and is made available to physicians in the form of a Software as a Service (SaaS) tool. To validate the method, patterns reported to the AI were compared with patterns rated as abnormal by the radiologist. Currently, the diagnostic platform includes up to 112 biomarkers and enables assessment of oncological status in less than a minute with an efficiency of 89%. KeyZell has completed training for the lung and breast cancer prototype and is currently training a module for AI-assisted diagnosis of colorectal cancer. In summary, O.P.S. as an effective diagnostic tool that supports physicians in their clinical decision-making and the development of a personalized treatment strategy.
A.I. Diagnosis
www.keyzell.com
Added on: 02-15-2024
Algorithm for early detection of increased risk of colon cancer in non-adherent patients
CompanyMedial EarlySign, Hod Hasharon, Israel(1)
Roche Deutschland Holding GmbH, Mannheim, Germany(2)
Roche Deutschland Holding GmbH, Mannheim, Germany(2)
Roche distributes ColonFlag, an algorithm developed by Medial Early Sign (MES), to aid in early detection of individuals with a higher probability of harboring colorectal cancer (CRC) than the general population. Colon Flag uses demographics data (birth year and gender) and lab results (current and past CBC results) of eligible patients. The data is sent anonymously to the navify® Algorithm Suite, where the algorithm computes a score which is then converted to a flag if it is above the cutoff value, indicating an increased likelihood of colorectal cancer compared to the general population. The physician should review the score in conjunction with his/her clinical judgment. The algorithm can be automatically integrated into existing IT systems, enabling simple and user-friendly access from the laboratory. In summary, the model enables an early risk assessment of the patient, thereby supporting doctors in clinical decision-making for further assessment. ColonFlag is not a diagnostic or screening device, but rather an indication of relative risk for colorectal cancer, thus a high score does not indicate malignancy or pathology. In addition, a low score for any given person does not indicate low risk or ruling out screening or further testing.
ColonFlag™
www.earlysign.com(1), www.roche.de(2)
Added on: 02-08-2024
Assay to study the pharmacokinetics-pharmacodynamics relationship in oncology
CompanyCN-BIO, Cambridge, United Kingdom
Modelling human tissue-specific biology and accurately predicting tumor response to human pharmacokinetic (PK) profiles in vitro is challenging. Therefore, poor correlation between preclinical PK and pharmacodynamic parameters and clinical studies is one reason for high drug failure rates.
CN-BIO's in vitro assay uses a microphysiological system (MPS), the PhysioMimix™ PK, which administers time-varying drug concentrations to human 3D tumor models, exposing them to a PK profile rather than a static concentration. Drug combinations, personalized medicine, dose schedules and PK/PD relationships can be tested in this way.
Until now, the effects of PK could only be studied in silico or in vivo. With the PhysioMimix oncology PK assay, the relationship between PK, PD and efficacy can be studied on a large scale in the laboratory for any 2D or 3D cell line, organoid or patient-derived tumor model.
What’s the alternative to Xenograft models in Oncology?
www.cn-bio.com
Added on: 03-16-2023
Assay-based screening platforms for identifying DNA-damaging agents and researching potential antagonists
CompanyPrediTox, Toulouse, France
To identify and evaluate exogenous and endogenous DNA-damaging agents that can, among other things, promote the development of cancer, the company PrediTox has developed the test procedures PrediProtect and PrediRepair. The screening platforms are based on an examination of the phosphorylation of the biomarker H2AX (γH2AX), through which different types of genotoxic compounds can be detected. The PrediProtect assay is specifically designed for the detection of reactive oxygen species (ROS). The test enables the determination of compounds that induce oxidative stress, as well as an evaluation of possible antioxidant counterparts that serve to defend against ROS and counteract the cell ageing process. The PrediRepair assay was developed to detect compounds that can help repair genetic damage that has already occurred. The Predi-assays from PrediTox enable a predictive safety assessment of active ingredients to be tested and can help to reduce drug-induced damage and improve the development of relevant (cancer) therapeutics.
Antioxidant effect and DNA repair
contact@preditox.fr
Added on: 10-19-2023
Automated development of personalized T cell therapies
CompanyActiTrexx GmbH, Mainz, Germany
To prevent and treat rejection reactions in stem cell transplants, the company ActiTrexx has developed an automated process for the development of personalized immune therapeutics (actileucel therapy). The development of graft-versus-host disease (GvHD) is primarily induced by activation of the donor's CD4+ T lymphocytes. The cellular therapeutic agent actileucel contains modified regulatory T cells that prevent this activation and can thereby prevent the development of GVHD. At the same time, they help to strengthen the patient's own immune system. By automating the various work steps (cleaning and preparation of donor leukapheresis, selection and activation of suitable T cells), ActiTrexx can make the vital medication available to the patient in just 24 hours. Actileucel has already been classified as an advanced therapy medicinal product (ATMP). The development is supported by, among others, the Federal Ministry of Education and Research and the European Regional Development Fund (ERDF). In summary, the method can help to develop an optimized treatment path for various serious diseases that require stem cell transplantation (such as cancer, autoimmune diseases and infections) and to significantly reduce the risk of life-threatening complications and the development of long-term side effects.
ActiTrexx. Activated treg for tolerance.
info@actitrexx.de
Added on: 04-09-2024
Bioprinted tumors for commercial drug testing
CompanyCarcinotech Ltd., Edinburgh, United Kingdom
Carcinotech offers assay-ready 3D-printed tumors for drug discovery, screening and preclinical testing. The innovative Carcino3D™ technology is validated and enables high throughput due to robotic manufacturing. Since the tumors are produced from patient biopsies, they reflect the heterogeneity of the original tumor. Tumors printed with Carcino3D™ are self-forming and ready for testing within 7-14 days of printing. They can be made to order, cryopreserved and shipped to other laboratories ready for testing. A team of 3D oncology experts also provides assay services for each agent using Carcino3D™ technology. In addition, tumors can be adapted to drug tests, e.g. for specific patient groups, mutation types, drug targets or treatments.
Personalised medicine & assay services
info@carcinotech.co.uk
Added on: 01-30-2023
Breast carcinoma organoids with adipose tissue on chip
Eberhard Karls University Tübingen, Tuebingen, Germany
Although adipose tissue is a crucial component that serves as an active endocrine organ in the breast cancer microenvironment, not much is understood in terms of adipocytes role in breast cancer progression and metastasis, as the recapitulation of tumor heterogeneity and its complex microenvironment constitutes a major challenge.
In this Micro OrganoLab project, human primary breast cancer organoids and adipose tissue are combined to generate an immunocompetent Breast-Carcinoma-on-Chip model. This platform will enable the investigation of the underlying mechanism of adipose-carcinoma interactions and the determination of their effect on breast cancer progression. Furthermore, patient-specific effects driven by disease states (healthy vs. obese vs. diabetic), age (pre- and postmenopausal), as well as ethnicity can be recapitulated in this model as a guide for personalised cancer treatment.
Tumor-on-Chip: Breast-Carcinoma-on-Chip
Peter Loskill
Added on: 03-05-2021
Bronchoscopy simulator with ultrasound module
CompanyKoken Co., Ltd., Tokyo, Japan
Besides a classic airway model for bronchoscopy, there is an ultrasonic model available, both are attached to a part-head model to train insertion and confirmation of the bifurcation of the oesophagus and bronchi. The model consists of a flexible rubber for a human-like texture which allows ultrafine bronchoscopy up to the quintenary bronchus. The ultrasonic model can, besides classic endoscopy, be used for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) training. Imaging of the lymph nodes and cancer metastases allows diagnosis and training of puncturing the target lymph node, as well as external cylinder method training.
Ultrasonic Bronchoscopy Simulator LM-099
https://www.kokenmpc.co.jp/english/
Added on: 12-07-2022
Cervix-on-a-Chip for human Papillomavirus research
Eberhard Karls University Tübingen, Tuebingen, Germany
Cervical cancer arises from persistent infection with high-risk human papillomavirus (HPV) which can lead to a precancerous lesion (cervical intraepithelial neoplasia) and squamous cell carcinoma. In contrast, low-risk HPV strains cause anogenital warts. However, most infections are cleared without any symptoms. This Micro OrganoLab project is focused on a patient-specific Cervix-on-a-Chip model that allows mechanistic research, disease modelling and drug testing.
Cervix/Skin/Mucosa-on-Chip: Cervix-on-Chip
Peter Loskill
Added on: 03-05-2021
Chemoproteomics platform for developing of targeted cancer drugs
CompanyBridGene Biosciences, San Jose, USA
The company BridGene Bioscienes specializes in the development of small molecule drugs against difficult-to-cure, protein-associated cancers. To identify potential active ingredients and their binding targets, the company has developed the chemoproteomics platform IMTAC™ (Isobaric Mass Tagged Affinity Characterization), which combines different technological approaches (covalent chemistry, chemical proteomics and quantitative mass spectrometry). The platform includes a comprehensive covalent library of small molecules loaded with various “warheads” targeting specific amino acids (cysteine, lysine, tyrosine, etc.). The molecules are brought into contact with living cells and penetrate into all cellular areas. IMTAC™ thereby enables effective screening of the entire proteome and direct isolation and identification of bound protein targets. Furthermore, the platform is able to specifically screen for disease-promoting mutants that are associated with certain oncological diseases (such as K-RAS G12C). In addition, the living cells are examined in different stimulation states. This also makes it possible to discover target binding targets in dynamic protein pockets that only develop in certain stimulus states. Using quantitative mass spectrometry, the potential protein targets are identified, their binding affinity to the molecule is assessed and a drug candidate ranking is created. In summary, the IMTAC™ platform proves to be an innovative solution for screening for previously unknown drug targets that can help improve the development of targeted cancer drugs.
Unlocking the proteome. Bridging new medicines with undruggable targets.
info@bridgenebiosciences.com
Added on: 01-18-2024
Colonoscopy model for diagnostics and therapy
CompanyKoken Co., Ltd., Tokyo, Japan
The realistic silicone-based colon model is for practising colonoscopy and its interventions. Replaceable parts like polyps can be attached in the ascending or descending colon and polypectomy and clipping hemostasis can be performed. A laterally spreading tumor can be reproduced in the ascending colon for observation and diagnostics. A small intestine is additionally available to train enteroscopic insertion into the small intestine as well as training with double or single balloon endoscopes.
Colonoscopy Simulator Type 2 LM-107
www.kokenmpc.co.jp/english/
Added on: 12-07-2022
Computer platform for the development of selective and targeted intracellular therapeutics
CompanySRI International, Menlo Park, USA
To optimize the development and delivery of intracellular biotherapeutics, SRI Biosciences has developed the computer-based platform FOX Three Molecular Guidance System. The platform enables cell-selective and targeted transport of large-molecule active ingredients into the interior of the cell by identifying unique peptide suppliers, the so-called MGS. The MGS are able to transport various therapeutic agents, such as protein-based toxins, antibodies, nucleic acids, liposomes and nanoparticles, to the desired cell types. After systemic administration and binding to the target cell, the MGS induce rapid cellular uptake of the bound cargo and deliver it to a specific target within the cell (also called a subcellular organelle). The computational platform's integrated data library currently includes information on 40 known MGS, selectively targeting nearly 20 different cell types and enabling targeted delivery to up to a dozen different subcellular drug targets. The FOX Three MGS platform was originally developed primarily to identify efficient targets for tumor suppression. The company has now expanded the database to other research areas and is working on the identification and development of MGS, which is intended to advance drug therapy options for liquid tumors and cardiac and metabolic diseases. Research is also underway to discover potential vaccine targets. In summary, the platform is a promising method that can help develop drugs that specifically target diseased cells without affecting the functional activities and structures of healthy cells.
FOX Three Molecular Guidance System (MGS)™
customer.service@sri.com
Added on: 11-30-2023
Development of GPR65 inhibitors for the treatment of solid tumor diseases
CompanyPathios Therapeutics Ltd., Abingdon, United Kingdom
Pathios Therapeutics specializes in the development of a new form of cancer therapeutics for the treatment of solid tumor diseases. The growth of cancer cells leads to the creation of an acidic tumor microenvironment (TME) through various metabolic processes. Based on immunological and genetic findings, an acidic pH value induces a functional change in the immune receptor GPR65. According to current knowledge, the pathological activation of GRP65 and the associated suppression of the immune response is closely linked to the low treatment response of cancer patients treated with T-cell checkpoint inhibitors. The company is therefore focusing on the development of drugs that inhibit the GPR65 signaling pathways and thereby promote the redevelopment of a healthy and immune-active microenvironment. In summary, human genetic research provides valuable starting points for advancing drug research and gaining new insights for optimized treatment of cancer patients.
Using human genetics to transform cancer outcomes
www.pathiostherapeutics.com
Added on: 04-24-2024
GAAD algorithm for early detection of hepatocellular carcinoma (HCC)
CompanyRoche Deutschland Holding GmbH, Mannheim, Germany
To optimize the early detection of hepatocellular carcinoma (HCC), Roche Deutschland Holding GmbH has developed the so-called GAAD algorithm. The method is suitable for patients who have been diagnosed with chronic liver disease and whose surveillance indicates an increased risk of HCC. For the risk assessment, two tumor biomarkers, Elecsys® AFP (alpha-fetoprotein) and Elecsys® PIVKA-II (protein-induced by vitamin K absence), are first quantitatively determined in a serum or plasma sample and then combined with age and transmitted anonymously based on the patient's gender to the company's navify® Algorithm Suite. Here, the algorithm calculates a risk score between 0 and 10, which is assessed using a clinically validated cut-off. A value ≥ 2.57 indicates an increased risk of liver cancer and requires further diagnostic clarification. So far it has been shown that the method is able to detect early-stage HCC with a sensitivity of 78.9% (67.6% - 87.7%) and a specificity of 91.3% (86.7% - 94.8%) can be recognized with certainty. Overall, the GAAD algorithm offers a promising method for optimizing the early detection of liver cancer and can thereby help to improve the survival rates of HCC patients. By using tumor biomarkers, the age and gender of the patient, the algorithm can detect an increased risk of HCC with a high degree of certainty and shows significantly higher sensitivity compared to existing methods.
GAAD Algorithmus
www.roche.de
Added on: 02-08-2024
Genotoxicity assay to identify carcinogenic agents
CompanyPrediTox, Toulouse, France
To identify potential cancer-causing agents, the company PrediTox has developed the PrediScreen genotoxicity assay. The technology is based on a study of the biomarkers H2AX (γH2AX) and H3 (pH3). The test is therefore able to reliably distinguish genotoxic (aneugenic and clastogenic) compounds from cytotoxic compounds. In addition, PrediScreen provides important information on the metabolic bioactivity of the active ingredients to be examined and shows a more sensitive measure of viability than the classic MTT assay. The proof of concept of the method was carried out on compounds recommended by ECVAM for the validation of alternative methods. Through the combined assessment of relevant genotoxic biomarkers, the PrediScreen provides more comprehensive information than previous established assays. In summary, the test optimizes toxicology screening and the safety assessment of new drugs and can help reduce drug-induced damage and improve the development of relevant (cancer) therapeutics.
Genotoxicity assay
contact@preditox.fr
Added on: 10-18-2023
Human 3D respiratory models
CompanyEpithelix, Geneva, Switzerland
MUCILAIR and MUCILAIR-HF from Epithelix are reconstructed complex 3D models of the human pulmonary epithelium and of nasal, bronchial and tracheal tissue. These are highly differentiated, metabolically and functionally active multicellular systems with mobile cilia and mucus production. They are generated from human primary cells obtained during surgery. In MUCILAIR-HF, these are still co-cultured with human airway fibroblasts. Different models are available: healthy epithelium, cigarette smoke, COPD, asthma, allergic rhinitis, cystic fibrosis (different gene variants); all reconstructed from primary cells of patients, phenotype preserved in culture. Also, a lung cancer model is available (lung epithelial cells, fibroblasts and adenocarcinoma cells), which remains functional over several months. In general, the models can be cultivated for more than 1 year (air-liquid interface). The cultures are delivered as ready-to-use cell culture plates, suitable for rapid assays and high throughput analyses with spectrophotometric detection.
www.epithelix.com
Added on: 05-25-2020
Human protein-based hydrogel solutions for creating physiological microenvironments
CompanyMetatissue, Ílhavo, Portugal
The company Metatissue specializes in the production of human, protein-based and chemically modified bioproducts for the development of three-dimensional in vitro microenvironments (hydrogels, sponges, bioinks). The PLMA photopolymerizable hydrogels are based on certain enzymes of the blood platelets (platelet lyases), whose bioactivity produces relevant proteins, cytokines and growth factors for mimicking a physiological, extracellular environment. The variable concentration of the PLMA 100 lyophilisate in the precursor solution and control of the gelation time enable the mechanical properties of the hydrogel to be modulated to suit individual research purposes. PMLA 100 can be used to cultivate various cells such as human stem cells (hSCs) or cancer cells (MG-63, SaOS-2 and A549). The hydrogel solutions enable tissue-specific modelling of a three-dimensional, bioactive extracellular environment in which the cultured cells are supplied with sufficient "nutrients" for relevant cell adhesion and proliferation processes over a period of up to 2 weeks. Metatissue's xeno-free hydrogels can help to improve the simulation and research of certain clinical pictures and thus (personalized) drug development by closely resembling the physiological conditions in vivo.
Human-based products for cell culture und tissue engineering
info@metatissue.com
Added on: 08-03-2023
Identification of new biomarkers for cancer and neurodegenerative diseases
CompanyVITO NV, Mol, Belgium
Biomarkers are used in prevention, screening for certain diseases and evaluating treatments. The VITO organization focuses on the identification of biomarkers for minimally invasive diagnostic applications, preferably using liquid biopsies (urine, blood and cerebrospinal fluid). In addition, however, fresh and fixed tissue material is also used for biomarker development using MALDI-based imaging. Within the scope of biomarker research, VITO focuses on the following areas:
1. Mainly for cancer research (bladder and lung cancer) and neurodegenerative diseases (dementia), VITO uses state-of-the-art mass spectrometry for the identification and detection of (panels of) protein biomarkers.
2. In the context of cancer research (especially lung and colorectal cancer), immunopeptides are analysed using immunopeptidomics with regard to applications in T-cell therapy, immunotherapy and personalised vaccination.
www.vito.be
Added on: 11-19-2021
IndivuServ: assistance for personalised oncology
CompanyIndivumed GmbH, Hamburg, Germany
IndivuServ is a service by Invidumed that offers high-quality cancer patient biospecimens and analysis for biomarker discovery, drug profiling, immune-oncology studies and clinical trials.
info@indivumed.com
Added on: 06-21-2021
IndivuTest: innovative diagnostics for personalised cancer therapy
CompanyIndivuTest GmbH, Hamburg, Germany
IndivuTest is a subsidiary of Indivumed andaims to decipher the biological basis of cancer using the latest scientific analysis methods and thus promote the individualization of cancer therapies in advanced stages of the disease. For this purpose, tumor samples from patients are analysed using elaborate and complex Multi-OMICs techniques combined with the latest scientific knowledge of drug development. The resulting individual patient profile enables the attending physician to select the presumably most effective therapeutic approach based on scientific criteria.
IndivuTest
info@indivutest.com
Added on: 06-21-2021
IndivuType: global multi-OMICs cancer database
CompanyIndivumed GmbH, Hamburg, Germany
IndivuType is a knowledge and discovery platform that combines genomics, transcriptomics, and proteomics datasets to enable cutting edge precision medicine approaches. IndivuType is a cancer database comprising patient-derived biospecimen and clinical data. It offers comprehensive visualization, statistical, bioinformatics and artificial intelligence tools for clinical evaluation, biomarker and target identification and validation. InviduType can be used to assist patient stratification and cohort design for clinical trials, as well as for multiple molecular aspects in basic and clinical research.
info-eu@indivumed.com
Added on: 06-21-2021
Lab-on-chip technology for migration assays and mechanobiological studies
CompanyCompreVie GmbH, Vienna, Austria
The CompreChip from CompreVie is based on a microfluidic lab-on-chip technology that enables controlled and fully automated (long-term) stimulation or wounding of different types of microtissue. A pneumatic system applies pressure to the cells cultivated in microchannels via a flexible membrane integrated into the chip. This allows different forms of mechanical stress, tissue injuries and trauma to be simulated. To analyse cellular processes, the platform is compatible with all common image analysis systems. One chip can be used to carry out up to 8 test series. The platform is suitable for a variety of different studies, ranging from cell migration studies to assess invasive substances to research into brain trauma or skin regeneration processes, making it a helpful and versatile tool for human-based in vitro research.
CompreChip
info@comprevie.com
Added on: 09-13-2023
Mechanosensitive high-throughput screening technology for cytotoxicity and drug studies
CompanyinnoVitro GmbH, Juelich, Germany(1)
Nanion Technologies GmbH, Munich, Germany(2)
Nanion Technologies GmbH, Munich, Germany(2)
The companies innoVitro and Nanion Technologies have jointly developed a high-throughput screening platform (FLEXcyte 96) to assess heart-damaging substances. The technology is based on specially designed 96 cell culture plates (FLEXcyte 96-well plates), whose wafer-thin, hyperelastic silicone membranes mimic the mechanical environment of the heart. The mechanosensitive environment has a positive effect on the maturation of human iPSC-derived heart cells. The maturation process can also be promoted by an optical stimulation method (CardioExcyte 96 SOLE), which can also be used to modulate the heartbeat behavior if required. The cultivation, monitoring and analysis of the contractility and electrophysiology of the cardiac microtissue is carried out with the CardioExcyte 96 (also developed by innnoVitro and Nanion), a software-based, highly sensitive screening technology with an integrated incubation system. CardioExcyte 96 technology enables non-invasive, label-free testing of acute and chronic cardiotoxicity. Cellular damage is recorded using basic impedance parameters. Electric field potentials (EFP) are recorded to assess disturbances in the heart's electrical excitation system. The method was validated by various cytotoxicity studies with human cardiomyocytes and other human cell lines (hepatocyte-like cells, cancer cells). The FLEXcyte 96 technology enables safe and rapid identification of (cardio)toxic agents and can help to accelerate drug development and prevent drug-induced damage.
FLEXcyte 96 and CardioExcyte 96 technologies
info@innoVitro.de(1), info@nanion.de(2)
Added on: 08-01-2023
Model for esophageal and gastric endoscopy
CompanyKoken Co., Ltd., Tokyo, Japan
The simulator is designed to practice endoscopy of the upper gastrointestinal tract. Due to a reconstruction of the oral and nasal cavities, both transoral and transnasal insertions are possible. The special rubber material reproduces a realistic endoscopic view that mimics the anatomy of the human body. Practising endoscopic examination of the oesophagus, stomach, and duodenum is possible. It is also possible to practice cannulation of the papilla during endoscopic retrograde cholangiopancreatography (ERCP). Gastric ulcers and early gastric cancer can be observed in the stomach as well as an ulcer in the duodenum. Four types of polyps can be attached and resection and bleeding control through clipping can be performed.
EsophagoGastroDuodenoscopy Simulator LM-103
www.kokenmpc.co.jp/english/
Added on: 12-07-2022
Organ-on-a-chip for research into hepatitis B infection
CompanyCN-BIO, Cambridge, United Kingdom
Hepatitis B is one of the most common infectious diseases worldwide, and the inflammation caused by HBV (Hepatitis B virus) can lead to cirrhosis, impaired liver function, and increased risk of liver cancer.
Currently, there are no long-term, high-functioning liver models that replicate the physiological environment required for HBV infection.
CN-Bio is culturing primary human hepatocyte cultures in a liver-on-a-chip model and infecting them with HBV. The infected cells have a survival time of at least 40 days, allowing the entire HBV life cycle to be recapitulated.
Infection with the viral inoculum results in long-term expression of antigens and viral DNA, allowing the anti-HBV response of drugs to be evaluated in a variety of modalities.
The PhysioMimix™ HBV assay shows increased expression of NTCP, the liver bile acid transporter that is critical for the initiation of HBV infection in the liver, which is not the case in 2D models. This assay also provides a greater cumulative increase in HBV surface antigen that better reflects the in vivo environment.
The innate immune system and cytokine responses following infection with HBV are similar to those observed in HBV-infected patients. This allows the study of signalling pathways important for immune evasion and the validation of biomarkers.
How does Hepatitis B virus infection cause human disease?
www.cn-bio.com
Added on: 03-16-2023
Patient-derived 3D mini tumors make it easier to choose treatment for cancer
CompanyASC Oncology GmbH, Berlin, Germany
To improve and facilitate the selection of a suitable drug therapy for cancer, ASC Oncology has developed the Reverse Clinical Engineering® test procedure. The personalized test procedure is suitable for patients with malignant, solid tumors, such as carcinomas or sarcomas. In the ASC Oncology laboratory, numerous three-dimensional “mini tumors” (PD3D® tumor organoids) are cultured from patients’ tumor tissue samples (obtained through biopsy or surgical resection), on which drugs can be safely tested. An automated screening platform with an integrated genetic data set analyses the exposed active ingredients and assesses cell viability. In addition, a sensitivity profile of the individual tumor model is created for each active ingredient tested. To make the predictions more precise, the test procedure can be expanded with additional options (e.g. sequencing, proteome analysis). Within an average of 28 days, the process generates meaningful results that are transmitted to doctors in accordance with data protection regulations. So far, it has been shown that Reverse Clinical Engineering® could correctly predict the effectiveness of drugs for tumor patients in up to 88% of cases and ineffectiveness in up to 100% of cases. In summary, it can be seen that the method enables an accelerated and personalized prediction of the effectiveness of various active ingredients, which can help doctors and their patients decide at an early stage on the safest and most effective drug treatment for cancer.
Krebs. Vor Behandlungsbeginn die Optionen testen. Im Labor. Ohne Nebenwirkungen.
www.asc-oncology.com
Added on: 01-18-2024
Perfused multi-organ panel for drug and tumor research
CompanyLena Biosciences, Atlanta, USA
Lena Biosciences has developed an organ panel (POP) that enables blood-like perfusion of cultured tissue in vitro. The microphysiological system consists of a multi-well plate (PerfusionPal) that is placed in a tray in which the cell cultures are independently perfused with a specially developed synthetic blood substitute. An integrated pump system enables simultaneous and controlled perfusion of up to 96 cell cultures. The blood-substitute contains a hemoglobin analogue, which ensures adequate oxygenation of the micro-tissues and stabilizes the pH of the cell medium. The blood substitute is immiscible with media, drugs or other reagents and can be collected after the experiment, sterile filtered and then reused for new studies. For the optimal development of microtissues and their long-term culture, the company has developed special cell culture scaffolds (SeedEZ) made of inert glass microfibers, whose pore systems allow the unhindered transport of nutrients, gases and metabolites, thus maintaining the physiological cell functions. The POP platform is suitable for conducting drug studies and for researching short-term and long-term metabolic interactions. In addition, the model can help improve cancer research by simulating vascularized tumors and their cellular environment.
Perfused organ panel
www.lenabio.com
Added on: 07-27-2023
Personalized tumor therapy with 3D cell culture and high-throughput flow cytometry
CompanyCELLphenomics, Berlin, Germany
CELLphenomics has developed a functional precision medicine platform that combines high-throughput flow cytometry with advanced automation and an optimized analysis pipeline.
CELLphenomics' ex vivo assays combine machine learning, automation and high-throughput flow cytometry to predict response to potentially approved or investigational therapies and ultimately determine which drugs or drug combinations are most effective for specific cancer types. To do this, PD3D® cell cultures or tumor organoids are grown from tumor biopsies within a short period of time. These are then treated in parallel with all possible cancer drugs and combinations of drugs. Classical chemotherapeutic agents as well as small molecules and therapeutic antibodies are tested individually or in combination. In addition, proteomic analysis can be performed.
CELLphenomics combines data generated by its flow cytometry platform with valuable patient clinical characteristics for patient stratification, enabling more precise treatment of patients with solid cancers. CELLphenomics uses cutting-edge cancer research technology to advance new therapies from target identification in drug discovery to clinical trial validation and successful clinical development.
info@cellphenomics.com
Added on: 07-30-2021
Self-learning AI accelerates drug development in cancer research
CompanyReverie Labs, Cambridge (Massachussetts), USA
The company Reverie Labs specializes in the development of AI-based software programs to accelerate and optimize drug development. To do this, the company combines different technological approaches that enable a predictive calculation of the efficacy and toxicity of compounds to be tested. To generate the predictions, the systems rely on information from huge, biochemically and physiologically relevant data sets. The programs also work on the principle of machine learning; i.e. they recognize new relevant compounds and mechanisms of action and automatically integrate them into their future calculations. This means that the programs continue to optimize themselves in an ongoing process. In addition, the platforms can help advance personalized medicine, as they are also able to process patient-specific data and take individual characteristics into account in their predictions. The method can be used in various approaches to drug development, such as evaluating the efficacy and safety of new drugs or generating information on the absorption, distribution, metabolism and excretion (ADME behaviour) of certain active ingredients. A particular focus of the company is the development of kinase inhibitors that are used to treat cancer. In summary, the AI-based programs prove to be a valuable and advanced method that can help accelerate (personalized) drug development and improve existing drug treatment options.
Pioneering new technology to develop next-generation cancer therapies
contact@reverielabs.com
Added on: 11-08-2023
The company offers diverse body parts made of special silicone rubber for human skin-like texture and realistic anatomical landmarks. They are suitable for training doctors and nurses in various techniques which are important in consultations and/or in the operating room. Available are a gluteal intramuscular injection model, injection and blood sampling practice arm model, central venous puncture trainer, faeces removal and glycerin enema training, airway suction model, tracheostomy management simulator, male and female catheterization and enema simulator, breast cancer inspection and palpation trainer, gynaecological examination simulator, pregnancy and newborn simulators.
Nursing / Caregiving Training Models & Pediatrics / Obstetrics and Gynecology Models
www.kokenmpc.co.jp/english/
Added on: 12-07-2022
Skin-on-chip model for dermatological and oncological exposure and drug studies
CompanyReact4Life, Genova, Italy
React4Life's skin-on-chip technology enables the study of skin reactions to certain stimuli, active ingredients and environmental factors under controlled exposure conditions. The three-dimensionally cultured mini skin cells recapitulate the structural and functional properties of human skin in vitro and can be used in various dermatological and oncological studies. The chip platform is suitable for researching the wound healing process of the skin after mechanical injuries or for evaluating cell damage caused by long-term UV irradiation. Furthermore, the development of skin diseases such as psoriasis, eczema or skin cancer can be simulated, and their progression can be analysed. Subsequently, the microfluidic models are suitable for efficacy testing in drug development, as well as the evaluation of possible drug-induced side effects and the identification of skin-damaging toxins. In summary, the skin-on-chip model is a versatile tool for gaining a better understanding of certain mechanisms of the skin and skin diseases and can help to accelerate the development of suitable drugs.
Skin-on-Chip
www.react4life.com
Added on: 10-24-2023
SpheroMed: Personalized cancer therapy, services for patients and doctors
CompanySpheroTec GmbH, Munich, Germany
With the help of the new SpheroTest, the scientists at SpheroMed can investigate the effect of medication on the cells of an individual tumor before the start of therapy. SpheroTest uses tumor tissue from each patient to produce personalised 3D tumor spheroids that are subjected to different cancer medications. This enables scientists and medical doctors to determine how sensitive each patient's tumor is to various medications. This information is very important for the attending physician in order to be able to draw up an optimal treatment plan for the individual patient.
SpheroMed: Die individualisierte Krebstherapie
Barbara Mayer
Added on: 05-22-2020
SpheroSelect: Testing of new cancer drugs on tumor organoids on behalf of pharmaceutical companies
CompanySpheroTec GmbH, Martinsried, Germany
SpheroSelect is a division of Spherotec GmbH in Martinsried near Munich. The scientists at SpheroSelect are commissioned by pharmaceutical and biotech companies with the company's proprietary spheroid microtumor technology to test the mode of action of drug candidates for oncology. The three-dimensional cell culture systems from SpheroSelect allow a realistic functional oncological testing.
SpheroSelect: Für ein realitätsnahes Drugprofiling
Barbara Mayer
Added on: 05-22-2020
T cell transduction to produce homogeneous immune cells for clinical research purposes
CompanyMiltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
The company Miltenyi Biotec has developed the fully automated CliniMACS Prodigy platform for an easily reproducible and standardized production process of genetically modified T cells to research their diagnostic and therapeutic potential against blood cancer. The platform includes two applications. CliniMACS Prodigy TCT (T cell transduction process) enables the production of chimeric antigen receptor T cells (CAR-T cells) from whole blood, peripheral blood mononuclear cells (PBMCs) or fresh leukapheresis. CliniMACS Prodigy TCT-LS (T cell transduction process- large scale) offers the user greater cell culture capacity and was developed for the production of T cell receptor cells (TCR T cells). After loading the system with the patient's blood samples, the CliniMACS Prodigy takes over all critical work steps. Magnetic beads integrated into the platform enable efficient isolation of CD4 and CD8 cells without activating them. At the same time, contaminated immune cells are safely removed from the system. To support the subsequent work steps (T cell activation, genetic modification of the isolated cells through viral transduction and their proliferation in culture), Milentyi offers specially developed reagents, media and additional components that promote transduction. By integrating sampling bags into the tubing system, researchers can also monitor and analytically evaluate the process progress and the quality of the cells throughout the entire manufacturing process using clinical flow cytometry. Overall, the method proves to be a comprehensive approach to the standardized development of clinically relevant immune cells that are needed to advance research into personalized T cell therapies against blood cancers (such as leukaemias or lymphomas).
Clinical-grade TCR engineered T cell and CAR T cell manufacturing via viral transduction
macs@miltenyibiotec.de
Added on: 02-15-2024
Tissue and liquid biobank of the National Center for Tumor Diseases (NCT)
Nationales Centrum für Tumorerkrankungen Heidelberg, Heidelberg, Germany
Employees of the tissue and liquid bank of the National Center for Tumor Diseases (NCT) collect and archive samples from cancer patients - such as tissue, blood or urine. They then make the material available to research at no charge.
NCT Tissue Bank
Esther Herpel
Added on: 05-22-2020
Vasularized Micro-Tumor Platform
CompanyAracari Biosciences, Irvine, USA
In Aracari’s platforms, self-assembled human blood vessels support tissue growth by delivering nutrients and drugs and cell therapies. The Vascularized Micro-Tumor platform is suitable for testing lead compound efficacy in inhibiting tumors growing in a biomimetic environment. Comprised of endothelial and stromal cells, the platform also includes human colon cancer, lung cancer or customized tumors of interest. Further oncology services include delivery of therapeutics to tumors via blood vessels, and measurement of tumor growth inhibition or tumor occupancy (T cells, oncolytic virus etc.). Immuno-oncology services are leukocyte vessel adhesion & extravasation, parallel delivery of leukocytes and immuno-oncological therapies (e.g. monoclonal antibodies), tumor occupancy by T cells (including CAR-Ts) or cytokine expression.
Vascularized Micro-Tumor (VMT™)
info@aracaribio.com
Added on: 12-19-2022
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[1029] https://aracaribio.com/technology/#vmt
