Mechanisms of myeloid cell driven pancreatic plasticity and carcinogenesis

Abstract Pancreatic cancer is almost invariably associated with the presence of an oncogenic, hyper-activated form of the KRAS gene. Oncogenic KRAS mutations are present in most human Pancreatic Intraepithelial Neoplasia (PanIN). Expression of oncogenic Kras in the pancreas epithelium of genetically engineered mouse models (GEMM) mimics human carcinogenesis, and provides a system to study early stages of the disease within the context of an intact microenvironment. The onset of pancreatic carcinogenesis requires dedifferentiation of epithelial cells to a duct-like, progenitor-like cell that is susceptible to oncogenic transformation. During this process, and throughout the progression of PanIN and cancer, the microenvironment surrounding the lesions is reprogrammed by tumor cells and, in turn, promotes carcinogenesis. Among the most abundant components of the PanIN and pancreatic cancer microenvironment are myeloid cells, including macrophages, granulocytes and several populations of immature myeloid cells. We have previously shown that myeloid cells are required for the onset of carcinogenesis, as they promote acinar cell dedifferentiation and sustained proliferation of early lesions. Further, in advanced disease, myeloid cells inhibit T cell mediated anti-tumor immune responses. However, myeloid cells can have the opposite effect, promoting tissue repair and remodeling rather than carcinogenesis. The goal of this proposal is to investigate the crosstalk between tumor cells and myeloid cells during the onset, progression and maintenance of pancreatic carcinogenesis. Using a combination of human patient samples and genetically engineered mouse models, as well as in vivo, in vitro and in silico approaches, we propose to map myeloid cell populations and functional status in the healthy pancreas, in PanIN, and in pancreatic cancer in human and mouse (Aim 1); define the function of myeloid cells at different stages of carcinogenesis (Aim 2); and reprogram myeloid cells to prevent/treat pancreatic cancer (Aim 3). Together these aims will advance our understanding of key cellular interactions that regulate pancreas carcinogenesis, and identify and test new combination therapy approaches for this disease.