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KFO 325:  Clinical relevance of tumor-microenvironment interactions in pancreatic cancer

Subject Area Medicine
Term since 2017
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 329116008
 
Despite significant research efforts in the last decades, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancer types known with an extremely poor prognosis. One hallmark of PDAC is its desmoplastic nature characterized by a high content of extracellular material deposition and the presence of numerous stromal cells, including activated fibroblasts/stellate cells, endothelial cells and various immune cells. The stromal contribution to the etiology of PDAC is complex and has undergone changing views in the recent past. However, it is clear that stromal cells are major determinants of the biology of pancreatic cancer. As such, they represent central players regulating the outspoken aggressiveness of PDAC with its early propensity for metastasis, its high degree of chemoresistance and the significant local host immune suppression. In Clinical Research Unit 325 (CRU 325), we seek to shed light on these central features of the disease and elucidate pathological mechanisms involved in the crosstalk of pancreatic tumor and stroma compartments. Our aim is to develop translatable approaches to target different stromal/immune cell populations and their corresponding signaling systems in order to combat the clinical failures associated with previous therapy regimes mainly focusing on the cancer cell compartment. Furthermore, we want to identify microenvironment-related and hitherto unknovm PDAC biomarkers, allowing for a future rational design of novel diagnostic and/or therapeutic approaches. Specifically, we will focus on the pathological roles of T cells. NK cells, macrophages and fibroblasts, using a sophisticated array of well standardized patient material, mouse models and in vitro systems. All patient material will be characterized by next generation sequencing including transcriptomics and PDAC gene mutation analysis, and by immune phenotyping and expert histological assessment. Ex vivo cell isolations as well as animal handling will be carried out centrally to ensure the highest comparability of data obtained in the different CRU projects, thereby maximizing the scientific output. These activities will be part of a central project, which is run by experts in their fields and which comprises patient sample biobanking, in vivo imaging and medicinal chemistry. All principal investigators participating in this CRU were selected based on their scientific excellence and their conceptual fit, integrating numerous clinical and basic research specialists into a synergistic translational network on stroma targeting and reprogramming. Several of these scientists have already successfully cooperated and published joint papers on various aspects of cancer biology, which in part provides the basis for this CRU. We expect that the CRU’s translational approach will lead to clinically relevant new insights into the mechanisms and molecules associated with therapy failure in PDAC. In addition, the CRU will structure and integrate research on
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