Pancreatic Cancer Development: Genetic and Immune Regulation

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Abstract (Overall): Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease whose mechanisms of development remain incompletely understood. Evidence suggests that pancreatic cancers may arise from acinar cells undergoing a process called acinar to ductal metaplasia (ADM) or from ductal cells to give rise to Pancreatic Intraepithelial Neoplasias (PanINs). How mutations or combinations of mutations promote PDAC development and the role of inflammation in the process still remains unclear. Moreover, interactions between immune cells, cancer- associated fibroblasts (CAFs) and cancer cells can promote PDAC development and progression, but much remains to be learned about how signaling between cells in the tumor microenvironment (TME) affects the stem cell compartment (`stemness') thought to underlie PDAC development and promotes immune evasion. Thus, multiple questions about fundamental mechanisms governing PDAC development persist. To address these challenges, our superb and highly interactive team will identify genetic and stromal (immune cells and CAFs) interactions and pathways that regulate the inception and progression of PDAC using innovative mouse models and human tissue-based approaches. We propose three Projects to address the following overall aims: 1. Identify the originating cell(s) and deconstruct genetic pathways underlying PDAC initiation 2. Discover immune signals that cross-talk with epithelial cells and CAFs to promote pancreas cancer development and stemness 3. Investigate the impact of tumor genetics on PDAC immunobiology and response to macrophage-targeted immunotherapy Effort on these projects will be organized through an Administrative and Biostatistics Core (A) and empowered by two Research Cores, focused on human tissue procurement (Core B), and use of high-dimensional imaging to measure cell and signaling interactions in tissues (CODEX; Core C). The participating investigators on this P01 lead teams that have collaborated productively for years and have generated compelling preliminary data that support the potential for unraveling the genetic and immune signaling mechanisms underlying PDAC development, and developing new immunotherapeutic strategies for PDAC, which has proven frustratingly resistant to immuno-based therapies. Our studies should broadly impact pancreas cancer biology and importantly, elucidate the reciprocal interactions between immune and non-immune compartments (epithelial, CAFs) in shaping the tumor microenvironment during disease evolution. accelerate discovery of novel diagnostic or preventive strategies for early-stage disease, or therapeutics for advanced PDAC.