Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.

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Declaration of Interests K.J.D. is currently an employee of Sherlock Biosciences. M.D.B. acknowledges research support from ViaCyte and Dexcom and serves on the medical advisory boards for Novo Nordisk and ARIEL Precision Medicine. A.L.G. has received honoraria from Merck and Novo Nordisk and has received research funding from Novo Nordisk. M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; he has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. R.G.K. is co-founder and a Scientific Advisory Board member of Elucidata; a Consultant/Advisory Board member for Agios, Janssen, BI-Lilly, and Pfizer; and a recipient of sponsored research agreements from Agios, AstraZeneca/BMS, Lilly, Pfizer, and Poxel. S.K. is a paid scientific advisor to AI Therapeutics. B.M.W. declares research funding from Celgene and Eli Lilly & Company, and consults for BioLineRx, Celgene, G1 Therapeutics, and GRAIL. T.J. is a Board of Directors member of Amgen and Thermo Fisher Scientific, co-founder and Scientific Advisory Board member of Dragonfly Therapeutics, co-founder of T2 Biosystems, and Scientific Advisory Board member of SQZ Biotech with equity holding in all five companies; he receives funding from the Johnson & Johnson Lung Cancer Initiative and Calico. C.S.F. reports receiving personal fees from Eli Lilly, Entrinsic Health, Pfizer, Merck, Sanofi, Roche, Genentech, Merrimack Pharma, Dicerna, Bayer, Celgene, Agios, Gilead Sciences, Five Prime Therapeutics, Taiho, KEW, and CytomX Therapeutics and receiving support from CytomX Therapeutics. M.D.M. acknowledges research support from Genentech.