dissertationPancreatic ductal adenocarcinoma (PDAC) is a devastating disease that is almost uniformly lethal within the first year of diagnosis and is the fourth leading cause of cancer deaths in the United States. Activating mutations in the KRAS protooncogene are found in nearly all human PDAC cases as well as in early putative PDAC precursor lesions, pancreatic intraepithelial neoplasias (PanINs). Modeling of PDAC has been achieved through expression of an activated Kras allele in mouse pancreas that results in PanINs similar to those found in humans. PanINs develop focally, however, despite ubiquitous expression of mutant Kras suggesting that other factors must be involved in Kras-induced PanIN formation. Due to ubiquitous expression of mutant Kras in the pancreas, it is unknown which cell type, or types, can contribute to PanINs. This thesis aims to understand the cellular events that lead to Kras-induced PanIN formation, and to identify the cellular origin of PDAC. We find that mature acinar cells of the adult pancreas are competent to form PanIN lesions following Kras activation, and this process is dramatically accelerated by co-activation of the Notch signaling pathway, which antagonizes differentiation during pancreas development, but is largely inactive in the adult. Lineage tracing indicates that Kras/Notch co-activation drives rapid acinar-to-ductal metaplasia (ADM) during which acinar cells take on a duct-like phenotype, providing a mechanism by which acinar cells can serve as the origin of a "ductal" tumor. During ADM, acinar cells lose expression of Ptf1a, a transcription factor that is considered the master regulator of acinar cell identity. To test the requirement for Notch in PanIN initiation we deleted the key Notch mediator RbpJ. Surprisingly, we found that loss of RbpJ resulted in an increase in Kras-induced PanIN formation. In the pancreas, however, RbpJ is part of the Ptf1a complex and we suspect that loss of RbpJ could alter Ptf1a complex function and perturb acinar cell differentiation, which could allow for Kras to drive PanIN formation. We formally tested whether loss of Ptf1a would allow for increased Kras-driven PanIN formation and found that, in the presence of activated Kras, Ptf1a null acinar cells rapidly formed PanINs. Expression loss of key differentiation factors resulting in ADM may in fact be the initial step towards Kras induced tumorigenesis. ADM is similarly seen during acute pancreatitis, although, ultimately, acinar differentiation is restored during the regeneration process. We find that inducing pancreatitis in animals harboring active Kras mutations results in rapid and robust PanIN initiatio
