Dysregulation of the islet hormone cholecystokinin drives obesity-associated pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer death in the United States with a 5-year survival rate of ~13%. Obesity is a key PDAC risk factor associated with increased incidence and decreased survival, but the mechanisms by which obesity promotes PDAC development and progression remain unclear. To study how obesity drives PDAC, our lab developed a novel genetically engineered mouse model of obesity-associated PDAC and found that obese mice had significantly increased disease burden relative to lean controls, a phenotype which was abrogated by early induced weight loss. Molecular analyses of the pancreata from obese mice showed marked upregulation of the peptide hormone cholecystokinin (CCK) in beta cells of the endocrine pancreas due to stress-responsive JNK/cJun signaling. CCK canonically promotes digestive enzyme release in exocrine acinar cells, the putative PDAC cell-of-origin, and acts as a survival factor in endocrine beta cells under conditions of increased insulin demand, such as obesity. Exogenous CCK stimulates acinar cell proliferation and ductal metaplasia, early prerequisite steps in PDAC development. Strikingly, we found that beta cell CCK overexpression was sufficient to enhance exocrine tumorigenesis in lean mice, phenocopying the effects of obesity and validating beta cell CCK as an independent driver of PDAC development. Conversely, pancreas-specific CCK knockout significantly abrogated exocrine tumorigenesis in obese mice similar to levels seen in lean mice. Critically, tumor burden was significantly positively associated with pancreatic CCK expression and negatively correlated with endogenous insulin production, suggesting that CCK, rather than insulin, drives obesity-associated tumorigenesis. Finally, treatment of obese mice with GLP-1 receptor agonists (GLP-1RAs), which augment glucose-stimulated insulin secretion and improve beta cell health, enhanced beta cell function and significantly decreased pancreatic CCK expression. Together, this work has established endocrine-exocrine CCK - rather than insulin - as a critical previously unappreciated mediator of obesity-driven PDAC and enabled the identification of novel translational approaches, including GLP-1RAs, to intercept obesity-associated PDAC development.