Project Summary Pancreatic cancer, the fourth most lethal cancer in the United States and rising, represents 3% of all cancer cases diagnosed per year but a disproportionate 8% of all cancer deaths per year. Because of a lack of early symptoms, pancreatic cancer tends to be diagnosed in later stages, often post-metastasis: fewer than 20% of patients are candidates for surgical resection. This contributes to a dismally low average 5-year survival rate of 9% across all stages at diagnosis; thus, higher resolution methods for early detection and abrogation are crucial. Pancreatic ductal adenocarcinoma (PDAC), a cancer of the exocrine cells of the pancreas, represents 93% of pancreatic cancer cases diagnosed per year. The initiation of PDAC is preceded by a characteristic cell fate change called acinar-to-ductal metaplasia (ADM). ADM is a naturally occurring, reversible process during pancreatic injury or inflammation. However, upon an oncogenic G12D mutation of the KRAS gene, a post-ADM state cannot be reversed, facilitating progression to a PDAC precursor state. ADM is mediated by changes in transcriptional and epigenetic regulation. In particular, the pluripotency factor Klf4 has been implicated as a master regulator of ADM. Epigenetic reprogramming has also been revealed as a major driver of PDAC progression and metastasis. A recent study found genome-wide Foxa1-mediated enhancer reprogramming to be a major driver of PDAC metastasis. Foxa1 and 2 are pioneer factors are known also to be necessary for pancreatic development. Furthermore, genome-scale reprogramming of histone modifications has also been demonstrated to drive the transition from local to distant metastasis. The role of cell fate-associated factors such as Klf4 and Foxa1 in cancer-associated transformations urges investigation of the relationship between pancreatic cell fate plasticity, reprogramming, and oncogenesis. Cell fate-related changes in the transcriptome and epigenome during ADM and PDAC metastasis have not been comprehensively profiled. The proposed project takes advantage of murine models of ADM, PDAC, and metastasis to characterize this relationship between changes in cell identity and oncogenesis. We aim to 1) determine how the transcriptome and epigenome change during ADM, and 2) determine the parallels in epigenetic dysregulation between PDAC progression and ADM. We hope that completion of this project will reveal novel properties of PDAC for potential early detection and therapeutic targeting.