Characterizing Cancer Associated Fibroblast Evolution, Programming, and Fibroblast-Epithelial Cell Crosstalk in Pancreatic Ductal Adenocarcinoma

Characterizing Cancer Associated Fibroblast Evolution, Programming, and Fibroblast-Epithelial Cell Crosstalk in Pancreatic Ductal Adenocarcinoma Pancreatic adenocarcinoma (PDAC) remains one of the deadliest cancer diagnoses in the United States with an abysmal overall 5-year survival rate of less than 15%. Unlike many other solid tumors such as breast or colorectal cancers, treatment of pancreatic cancer is not dictated by molecular subtypes of disease. A major barrier to developing precision-based treatments for pancreatic cancer has been the pancreatic tumor microenvironment (TME). Cancer associated fibroblasts (CAFs) comprise >80% of the TME and can either be tumor-promoting or tumor-suppressive in a highly context- dependent manner. There is a critical unmet need to characterize CAF development and polarization in PDAC to help develop effective treatments. In this proposal, we will test the central hypothesis that CAFs co-evolve with epithelial cells during tumor progression, and that the molecular subtype of PDAC can dictate stromal CAF composition. This hypothesis will be investigated through the following specific aims: (1) Characterize the evolution of fibroblasts from normal pancreatic tissue to adenocarcinoma. (2) Dissect the effects of fibroblast polarization by PDAC and assess subtype specific programming. Together, this work will generate a temporal map of CAF evolution and can help clarify subtype-specific TME features that can pave the way for new therapies.