Mechanisms of Molecular Carcinogenesis – Volume 2
Edited by Johannes Haybaeck - with an Entire Chapter on Our PD3D models written by Dr. Alessandra Silvestri
This second volume complements the first by presenting and concisely explaining the carcinogenesis of various tumor entities such as non-melanoma skin cancers, bone and soft tissue tumors, pancreatic cancers, hepatocellular cancer and neuroendocrine tumors. As in volume one, each chapter illuminates the similarities and dissimilarities of changed signaling pathways in the different organ systems and depicts potential therapeutic strategies. The focus of volume two lies on the presentation of modern molecular biological techniques for diagnosis, as well as strategies for biomarker identification and validation. Furthermore, it discusses potential therapeutic targets and individualized treatment strategies, offering a valuable resource for all basic scientists and medical researchers interested in translational cancer research.
BIONNALE is the largest networking event for life sciences and healthcare industries in the German capital region.
Representatives from academia and industry attend the annual event to identify, engage and enter into strategic partnerships. The networking character is one strength of the multi-sessional, international event which was attended by more than 800 participants in 2016. BIONNALE 2017 will again focus on biotechnology, pharmaceuticals and medical technology. Cross-sector co-operation is the key word for the HealthCapital region.
Entrepreneurs, Academics & Entrepreneurial Academics succeed in Berlin
With Berlin's plethora of life science research and academia, opportunities abound for biotech entrepreneurs. Here's how the city bridges the gap between science and business!
Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling > 4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups due to the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.
The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells.
Several lines of evidence have suggested that stemness and acquired resistance to targeted inhibitors or chemotherapeutics are mechanistically linked. Here we observed high cell surface and total levels of nerve growth factor receptor/CD271, a marker of melanoma-initiating cells, in sub-populations of chemoresistant cell lines. CD271 expression was increased in drug-sensitive cells but not resistant cells in response to DNA-damaging chemotherapeutics etoposide, fotemustine and cisplatin. Comparative analysis of melanoma cells engineered to stably express CD271 or a targeting short hairpin RNA by expression profiling provided numerous genes regulated in a CD271-dependent manner. In-depth analysis of CD271-responsive genes uncovered the association of CD271 with regulation of DNA repair components. In addition, gene set enrichment analysis revealed enrichment of CD271-responsive genes in drug-resistant cells, among them DNA repair components. Moreover, our comparative screen identified the fibroblast growth factor 13 (FGF13) as a target of CD271, highly expressed in chemoresistant cells. Further we show that levels of CD271 determine drug response. Knock-down of CD271 in fotemustine-resistant cells decreased expression of FGF13 and at least partly restored sensitivity to fotemustine. Together, we demonstrate that expression of CD271 is responsible for genes associated with DNA repair and drug response. Further, we identified 110 CD271-responsive genes predominantly expressed in melanoma metastases, among them were NEK2, TOP2A and RAD51AP1 as potential drivers of melanoma metastasis. In addition, we provide mechanistic insight in the regulation of CD271 in response to drugs. We found that CD271 is potentially regulated by p53 and in turn is needed for a proper p53-dependent response to DNA-damaging drugs. In summary, we provide for the first time insight in a CD271-associated signaling network connecting CD271 with DNA repair, drug response and metastasis.
We now have available more than 175 PD3D cell culture models.
Customers can now choose from a variety of more than 175 different tumor models, including sarcomas and mesotheliomas.
cpo has entered a partnership with Austrian competence center CBmed
CBmed, an Austrian funded competence center, links excellent research infrastructure, scientific expertise, medical knowledge, national and international industry partners for systematic medical biomarker research.
CBmed brings together scientific experts with leading pharmaceutical, diagnostic, medical-technology and IT industry partners. In addition, CBmed has a strong network in the area of Biobanking including the largest Biobank in Europe, Biobank Graz, and the European Biobanking network BBMRI-ERIC. CBmed research projects will identify new biomarkers, validate potential biomarkers and conduct translational biomarker research for products to be used in clinical practice.
CBmed will develop easily applicable, targeted, minimally invasive biomarkers for better diagnosis, better therapy monitoring and a more personalized treatment of patients.
The application of patient-derived three-dimensional culture systems as disease-specific drug sensitivity models has enormous potential to connect compound screening and clinical trials. However, the implementation of complex cell-based assay systems in drug discovery requires reliable and robust screening platforms. Here we describe the establishment of an automated platform in 384-well format for three-dimensional organoid cultures derived from colon cancer patients. Single cells were embedded in an extracellular matrix by an automated workflow and subsequently self-organized into organoid structures within 4 days of culture before being exposed to compound treatment. We performed validation of assay robustness and reproducibility via plate uniformity and replicate-experiment studies. After assay optimization, the patient-derived organoid platform passed all relevant validation criteria. In addition, we introduced a streamlined plate uniformity study to evaluate patient-derived colon cancer samples from different donors. Our results demonstrate the feasibility of using patient-derived tumor samples for high- throughput assays and their integration as disease-specific models in drug discovery.