Cell
Volume 181, Issue 4, 14 May 2020, Pages 832-847.e18
Journal home page for Cell

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

https://doi.org/10.1016/j.cell.2020.03.062Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Obesity accelerates oncogenic Kras-driven pancreatic ductal tumorigenesis in mice

  • Genetic or dietary weight loss intercepts pancreatic cancer progression

  • Obesity is associated with aberrant pancreatic islet cholecystokinin expression

  • Islet cholecystokinin overexpression drives pancreatic ductal cancer development

Summary

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.

Keywords

pancreatic cancer
obesity
cholecystokinin
pancreatic islets
beta cells
tumor microenvironment
genetically engineered mouse models
leptin

Cited by (0)

17

Present address: Genentech, 340 Point San Bruno Boulevard, South San Francisco, CA 94080, USA

18

Present address: Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA

19

These authors contributed equally

20

Lead Contact