How ferroptosis and ferroptosis-response-pathways shape the immune landscape in pancreatic ductal adenocarcinoma (PDAC)

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with increasing incidence and low survival rate. The poor prognosis is mainly due to limited treatment options and a difficult prediction of therapeutic response and resistance. Regulated cell death has essential functions in organ homeostasis, but also in chronic diseases or carcinogenesis. It is based on a defined molecular machinery that can be modulated by pharmacological or genetic intervention. In the past, several in vitro studies have shown a possible relevance of ferroptosis - a newly discovered form of regulated cell death - in the development of PDAC, but none of these studies reflected the actual situation in PDAC. Thus, it is currently unclear whether ferroptose activation could have a pathophysiological relevance in PDAC.In our previous projects we have gained important insights into the influence of cell death signaling pathways and their interaction with inflammatory signaling pathways in the regulation of acute and chronic diseases of the gastrointestinal system. In this grant application, we will transfer the concepts from our previous research to the field of PDAC development in close cooperation with the planning group and other applicants, and thereby investigate the role of ferroptosis in PDAC development and treatment. By applying different strategies we want to systemically investigate whether ferroptosis regulates the development of PDAC and whether it can influence the sensitivity of PDAC to standard chemotherapy and immunotherapy. The basic hypothesis of the proposal is based on promising preliminary data that we were able to collect in preparation of this proposal. In this application we will focus on the following three points:1. characterization of the pathophysiological significance of ferroptose activation in human PDAC organoids2. investigation of the effects of ferroptose activation and ferroptose-dependent immunological signatures on PDAC development and possible treatment concepts in vivo.3. correlation of findings from mouse models with PDAC patient samples.For the successful execution of the application, important experimental systems and genetically modified mouse models have already been generated and cooperations with potential participants of this initiative have been established, so that an immediate start and effective execution of the project is possible. After successful completion of these work packages we expect a new and comprehensive view on the pathophysiological role of ferroptosis in the development and treatment of PDAC.