Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma

Cell. 2020 May 14;181(4):832-847.e18. doi: 10.1016/j.cell.2020.03.062. Epub 2020 Apr 17.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinoma, Pancreatic Ductal / etiology*
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Disease Models, Animal
  • Disease Progression
  • Endocrine Cells / metabolism
  • Exocrine Glands / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Obesity / genetics
  • Obesity / metabolism*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Signal Transduction / genetics
  • Tumor Microenvironment / physiology