Targeting pancreatic endocrine-exocrine signaling in cancer development with incretin mimetics

Incretin mimetics, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), have revolutionized obesity and diabetes treatment, become first-line anti-obesity medications, and may soon be more widely used for other indications including cardiovascular and renal disease prevention, neurodegeneration, and addiction. Like bariatric surgery, GLP-1RAs may decrease the incidence of obesity-driven cancers, including pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with few effective therapies. However, several clinical trials and real-world studies based on the FDA Adverse Event Reporting System (FAERS) have raised the question of whether GLP-1RAs enhance PDAC risk. As persons with obesity and diabetes are the typical population treated with GLP-1RAs, it has been challenging to disentangle the effects of the medications themselves versus these established risk factors on possibly increasing PDAC risk. Similarly, studies in preclinical models have shown inconsistent results and largely lacked the right genetic and physiologic context to faithfully study the impact of GLP-1RAs on pancreatic tumorigenesis. Therefore, whether and how incretin mimetics modulate PDAC risk remains unknown. GLP-1R, the target receptor for GLP-1RAs, is highly expressed in endocrine beta (β) cells and to a lesser degree in exocrine acinar cells. Although PDAC is primarily thought to arise from acinar cells, our lab has established a critical role for dysfunctional β cell expression of the hormone cholecystokinin (CCK) in driving obesity-associated PDAC progression through a previously unappreciated endocrine-exocrine signaling axis. In both humans and mice, GLP-1RAs improve β cell health through direct β cell GLP-1R signaling and weight reduction. Conversely, GLP-1RAs stimulate acinar cell proliferation and digestive enzyme production and secretion, mechanisms linked to CCK-induced tumorigenesis. Therefore, we hypothesize that GLP-1RAs act directly on acinar and β cells to promote or suppress PDAC tumorigenesis, respectively, and that the balance of these opposing effects in different physiologic contexts determines PDAC risk. The studies in Aim 1 utilize powerful genetically engineered mouse models that closely recapitulate human PDAC progression, multiple obesity paradigms, modern FDA-approved GLP-1RAs used in obesity treatment, single-cell sequencing and multimodal computational analyses, and islet functional studies to define whether and how GLP-1RAs alter β cell state and function to modulate obesity-driven exocrine tumorigenesis. The proposed work in Aim 2 leverages sophisticated genetic methods, molecular studies, and state-of-the-art primary cultures to determine how GLP1RAs perturb acinar cell fate and function to regulate pancreatic tumorigenesis in the lean context. Together, these experiments will transform our understanding of how GLP-1RAs alter pancreatic endocrine and exocrine cell function to govern PDAC development in different physiologic contexts, enabling targeted deployment of incretin mimetics to decrease the risk of this highly lethal and recalcitrant cancer.