The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in western countries. It is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. PDAC is characterized by a profound inflammatory tumor microenvironment (TME) comprising various non-neoplastic cells e.g., myofibroblasts, macrophages, T cells and endothelial cells which can exhibit different functional phenotypes. Furthermore, the microbiome is altered in the tumor and other body compartments of PDAC patients adding to the great TME heterogeneity and its impact on PDAC development, progression and therapy responses. This review summarizes the recent knowledge on the diverse phenotypes of these different stromal components. A better understanding of tumor cells as well as TME heterogeneity and considering tumor-suppressing and tumor-promoting phenotypes might provide an important step towards a more effective treatment for this highly malignant tumor. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients.