PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death and soon to become the second in the next few years. Numerous epidemiologic studies have shown that obesity increases the risk of developing and dying of PDAC. Given the rise in worldwide obesity rates, a better understanding of the mechanisms by which obesity promotes PDAC progression is necessary. To study how obesity drives PDAC, our lab recently combined a well-established genetic model of obesity with an oncogenic Kras-driven pancreatic cancer model and showed increased tumor burden and decreased survival compared to non-obese controls. Obese mice exhibited aberrant expression of the neuropeptide hormone cholecystokinin (CCK) in pancreatic islet beta (b) cells, the latter of which was sufficient to enhance Kras-driven pancreatic tumorigenesis. These results uncovered a novel mechanism of obesity-driven PDAC by local hormonal signaling between endocrine islets and exocrine acinar cells. Therefore, my overall goal is to elucidate the cellular and molecular mechanisms by which islets adapt in response to obesity and in turn promote PDAC progression through endocrine-exocrine hormonal signaling. In Aim I, I will perform lineage tracing studies in vivo and in silico to identify the cell-of-origin that gives rise to b cells mis-expressing hormones, such as CCK. In Aim II, I will determine whether loss of transcription factors required for b cell identify lead to aberrant hormone expression in mouse insulinoma (insulin-producing) cells and primary human b cells using genetic knockdown experiments and chromatin immunoprecipitation. Lastly, in Aim III, I will perform in vivo gain-of-function and loss-of-function experiments using islet specific gene manipulation by adeno-associated viruses to evaluate the pro-tumorigenic potential of hormones beyond CCK that are overexpressed in b cells in obesity. Together, these studies will reveal novel endocrine adaptations that could be targeted to halt obesity-driven pancreatic exocrine tumorigenesis. In addition, through the acquisition of new technical skills in this project, extensive mentorship (from her sponsor, co-sponsor, and collaborators), interactions within an outstanding scientific environment, participating in advanced classes and workshops, and attendance and presentation at conferences and seminars, the comprehensive training plan will markedly broaden the applicant’s skillset in preparation to be a successful independent research scientist.