Coordination Funds

尽管在过去的几十年中进行了大量的研究工作，但胰腺导管腺癌（PDAC）仍然是已知的最致命的癌症类型之一。PDAC的一个标志是其促结缔组织增生的性质，其特征在于高含量的细胞外物质沉积和大量基质细胞的存在。另一个更功能性的标志代表PDAC的深刻的免疫逃避，其反映为对免疫疗法的固有抗性。现在，基质细胞是胰腺癌生物学的主要决定因素是无可争议的。因此，它们代表调节PDAC的公开攻击性的核心参与者，其具有早期转移倾向、高度的化学抗性和显著的局部宿主免疫抑制。在其第一个资助期间，临床研究单位325（CRU 325）揭示了疾病的这些基本特征，并在阐明胰腺肿瘤和间质室串扰所涉及的病理机制方面取得了令人兴奋的进展。这一科学进步是由参与的CRU成员成功地建立了一个高度协同和富有成效的结构框架，并得到了强大的核心技术项目和资源的支持。在这个更新提案中，我们的目标是继续这一研究路线，开发针对不同基质/免疫细胞群体及其相应的信号系统，通过使用一系列复杂的标准化患者材料、小鼠模型和体外系统。此外，关于微生物组及其与宿主细胞相互作用的研究已被新加入我们的研究组合。同样，中央PDAC生物样本库的可用性，以及下一代测序（包括转录组学和PDAC驱动基因突变分析）以及免疫表型和专家组织学评估的特征，对于子项目的成功至关重要。患者源性癌症类器官的建立以及动物处理将集中进行，以确保不同CRU项目中获得的数据具有最高的可比性。这些活动将得到三个中心项目的支持，包括患者样本生物库、病理学和体内成像。我们希望CRU的转化方法将导致临床相关的新见解的机制和分子与治疗失败的PDAC。此外，CRU还在当地医学院构建和整合了PDAC中肿瘤-微环境相互作用的研究，并为该领域的新研究活动提供了重要的新动力。总之，由于基础和临床科学PI之间的密切合作，CRU处于有利地位，可以实现将临床前研究成果转化为临床的长期目标，以改善PDAC患者的诊断和治疗。

Despite significant research efforts in the last decades, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancer types known. One hallmark of PDAC is its desmoplastic nature characterized by a high content of extracellular material deposition and the presence of numerous stromal cells. Another, more functional hallmark represents the profound immune evasion of PDAC which is reflected by the inherent resistance to immune therapies. It is now undisputed 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. During its first funding period, the Clinical Research Unit 325 (CRU325) has shed light on these fundamental features of the disease and has made exciting progress in the elucidation of pathological mechanisms involved in the crosstalk of pancreatic tumor and stroma compartments. This scientific advancement was made possible by the participating CRU members successfully establishing a highly synergistic and productive structural framework, supported by strong central technology projects and resources.In this renewal proposal we aim to continue this line of research, developing translatable approaches to target different stromal/immune cell populations and their corresponding signaling systems by using a sophisticated array of well standardized patient material, mouse models and in vitro systems. Furthermore, studies on the microbiome and its interplay with host cells have been newly added to our research portfolio. Again, the availability of a central PDAC biosample repository, well-characterized by next generation sequencing including transcriptomics and PDAC driver gene mutation analysis as well as by immune phenotyping and expert histological assessment will be of paramount importance for the success of the subprojects. Establishment of patient-derived cancer organoids as well as animal handling will be carried out centrally to ensure the highest comparability of data obtained in the different CRU projects. These activities will be supported by three central projects covering patient sample biobanking, pathology and in vivo imaging. 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 has structured and integrated research on tumor-microenvironment interactions in PDAC at the local medical faculty and has given important new impetus for new research activities in this area. In summary, due to the close cooperation between basic and clinical science PIs, the CRU is well positioned to achieve its long-term goal of translating preclinical research findings into the clinic in order to improve diagnosis and treatment of PDAC patients.