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.