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

胰腺导管腺癌（PDAC）是一种侵袭性肿瘤，发病率高，生存率低.预后不良主要是由于有限的治疗选择和难以预测的治疗反应和耐药性。调节性细胞死亡在器官稳态中具有重要功能，但也在慢性疾病或癌发生中具有重要功能。它是基于一个明确的分子机制，可以通过药理学或遗传干预进行调节。在过去，一些体外研究已经显示了铁凋亡（一种新发现的调节性细胞死亡形式）在PDAC的发展中可能的相关性，但这些研究都没有反映PDAC的实际情况。因此，目前还不清楚是否ferroptose激活可能有病理生理学相关性PDAC.In我们以前的项目中，我们已经获得了重要的见解细胞死亡信号通路的影响，并与炎症信号通路在急性和慢性疾病的胃肠系统的调节。在这项资助申请中，我们将与规划小组和其他申请人密切合作，将我们以前研究的概念转移到PDAC开发领域，从而研究铁凋亡在PDAC开发和治疗中的作用。通过应用不同的策略，我们希望系统地研究铁凋亡是否调节PDAC的发展，以及它是否可以影响PDAC对标准化疗和免疫治疗的敏感性。该提案的基本假设是基于我们在准备该提案时收集的有希望的初步数据。在这个应用程序中，我们将重点关注以下三点：1。表征人PDAC类器官中果糖激活的病理生理学意义2。研究果糖活化和果糖依赖性免疫特征对PDAC发展的影响以及体内可能的治疗概念。小鼠模型的发现与PDAC患者样本的相关性。为了成功执行该应用程序，已经生成了重要的实验系统和转基因小鼠模型，并与该计划的潜在参与者建立了合作关系，因此可以立即启动并有效执行该项目。在成功完成这些工作包后，我们期待着对PDAC的发展和治疗中铁凋亡的病理生理作用有一个新的全面的看法。

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.