Abstract
Abstract Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how obesity contributes to pancreatic cancer development is not well understood. Moreover, whether and at what point weight loss or other obesity-related interventions may impact PDAC progression remains largely unexplored, with significant implications for prevention and treatment. Leveraging an autochthonous genetically engineered model of PDAC, we demonstrate that obesity plays a stage-specific causal and reversible role in early PDAC progression. Molecular and histologic analyses reveal prominent microenvironmental alterations in tumors from obese mice, including increased inflammation and fibrosis and evidence for marked pancreatic islet cell adaptation. In particular, we identify aberrant expression of the peptide hormone cholecystokinin (CCK) in pancreatic islets in tumors as an adaptive response to obesity and show that islet CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Together, these studies link obesity, changes in the local microenvironment, and tumorigenesis and implicate islet-derived hormones beyond insulin in PDAC development. Furthermore, the reversible nature of these adaptations supports the potential of antiobesity strategies to intercept PDAC early during progression. Citation Format: Katherine Minjee Chung, Jaffarguribal Singh, Lauren Lawres, Kimberly Judith Dorans, Rebecca Robbins, Arjun Bhutkar, Ana Babic, Sara A. Vayrynen, Andressa D. Costa, Jonathan A. Nowak, Daniel T. Chang, Richard F. Dunne, Aram F. Hezel, Albert C. Koong, Joshua J. Wilhelm, Melena D. Bellin, Vibe Nylander, Anna L. Gloyn, Mark I. McCarthy, Brian M. Wolpin, Tyler Jacks, Charles S. Fuchs, Mandar Deepak Muzumdar. Microenvironmental adaptations drive obesity-associated pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A35.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
