Journal
CELL
Volume 181, Issue 4, Pages 832-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.03.062
Keywords
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Categories
Funding
- Lustgarten Foundation Research Investigator Grant
- Cancer Center Support (core) from the NCI [P30-CA016359, P30-CA014051]
- Yale Cancer Center
- Yale Cancer Innovations Award
- NIH Director's New Innovator Award [DP2-CA248136]
- National Institute for Health Research, Oxford Biomedical Research Centre
- NIH/NIGMS [T32-GM007499]
- NICHD [F31-HD097958]
- NCI [K07-CA222159, K08-CA2080016]
- Bob Parsons Fellowship
- Wellcome Senior Fellow in Basic Biomedical Science
- Oxford, Wellcome Trust [095101, 200837, 106130, 203141]
- Medical Research Council [MR/L020149/1]
- European Union Horizon 2020 Programme (T2D Systems)
- NIDDK [U01-DK105535, U01-DK085545, P30-DK045735, R01-DK110181]
- Wellcome [090532, 098381, 212259]
- NIHR [NF-SI-0617-10090]
- NIH [R01-GM130847, U01-CA210171]
- HIPC [2U19AI089992]
- Chan Zuckerberg Initiative [CZF2019-002440]
- Hale Family Center for Pancreatic Cancer Research
- Lustgarten Foundation
- Stand Up To Cancer
- Noble Effort Fund
- Wexler Family Fund
- Promises for Purple
- Conquer Cancer Foundation-American Society for Clinical Oncology (CCF-ASCO) Young Investigator Award
- NIH Loan Repayment Program
- MRC [MR/L020149/1] Funding Source: UKRI
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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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