Abstract LT013: Endocrine-exocrine signaling is a driver of obesity-associated pancreatic ductal adenocarcinoma

Abstract

Abstract Obesity is a major modifiable host risk factor for pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer death in the United States and a major cause of morbidity and mortality worldwide. Despite the rapid rise in the prevalence of obesity, surprisingly little is known about how it drives tumor progression. Therefore, deciphering these mechanisms is not only a societal imperative but also represents a key untapped target to develop novel strategies for PDAC prevention and therapy. Motivated by this gap in knowledge, we developed a rapid and reversible autochthonous mouse model of obesity-associated PDAC that recapitulates the genetic and histologic features of the human disease. We showed that obesity accelerates pancreatic tumorigenesis, while genetic or dietary weight loss intercepts tumor development, consistent with a causal and reversible role for obesity in early PDAC progression. By analyzing human and murine biospecimens, we defined obesity-driven microenvironmental alterations that foster tumorigenesis rather than new driver mutations, including significant inflammation, fibrosis, and islet adaptation. Specifically, we identified aberrant pancreatic beta cell expression of the hormone cholecystokinin (CCK) in response to obesity and showed that islet CCK itself promotes oncogenic Kras-driven pancreatic cancer. We further observed that CCK expression and tumor progression correlated with hyperglycemia, beta cell dysfunction, and reduced insulin secretion, suggesting that islet adaptations apart from insulin may drive tumorigenesis in obesity. By performing single-cell RNA-sequencing of islets from genetic and diet-induced obesity models, we have further nominated molecular mechanisms of CCK induction in beta cells and are testing their functional role in PDAC progression. Together, our findings argue that PDAC development is driven by local obesity-associated alterations in the tumor microenvironment, implicate a previously unappreciated endocrine-exocrine signaling axis beyond insulin in this process, and highlight the possibility of targeting the endocrine pancreas as a novel approach to intercept pancreatic exocrine tumorigenesis. Citation Format: Cathy Garcia, Jaffarguriqbal Singh, Lauren Lawres, Sherry Agabiti, Daniel B. Burkhardt, Alexander Tong, Rebecca Cardone, Richard G. Kibbey, Smita Krishnaswamy, Mandar D. Muzumdar. Endocrine-exocrine signaling is a driver of obesity-associated pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT013.