Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma
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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.
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Self-citation
- Authors
- Chung, K. M., Singh, J., Lawres, L., Dorans, K. J., Garcia, C., Burkhardt, D. B., Robbins, R., Bhutkar, A., Cardone, R., Zhao, X., Babic, A., Vayrynen, S. A., Dias Costa, A., Nowak, J. A., Chang, D. T., Dunne, R. F., Hezel, A. F., Koong, A. C., Wilhelm, J. J., Bellin, M. D., Nylander, V., Gloyn, A. L., McCarthy, M. I., Kibbey, R. G., Krishnaswamy, S., Wolpin, B. M., Jacks, T., Fuchs, C. S., & Muzumdar, M. D.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Yale University (US)
- Brigham and Women's Hospital (US)
- Stanford Cancer Institute (US)
- University of Rochester Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Minnesota Medical Center (US)
- Centre for Human Genetics (GB)
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Yale Cancer Center (US)
- Corresponding author
- Muzumdar, Mandar Deepak
- ORCID
- Chung, Katherine Minjee
- Singh, Jaffarguriqbal
- Lawres, Lauren
- Burkhardt, Daniel B.
- Bhutkar, Arjun
- Zhao, Xiaojian
- Nowak, Jonathan A.
- Chang, Daniel T.
- Dunne, Richard F.
- Hezel, Aram F.
- Koong, Albert C.
- Wilhelm, Joshua J.
- Bellin, Melena D.
- Nylander, Vibe
- Gloyn, Anna L.
- McCarthy, Mark I.
- Kibbey, Richard G.
- Krishnaswamy, Smita
- Wolpin, Brian M.
- Jacks, Tyler
- Fuchs, Charles S.
- Muzumdar, Mandar Deepak
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 181
- Issue
- 4
- Pages
- 832-847.e18
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7266008
- OpenAlex
- W3016562543
- Cited by
- 150
- References
- 92
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 27 · 2023: 22 · 2022: 33 · 2021: 17 · 2020: 11
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Lustgarten Foundation (P30-CA014051, P30-CA016359)
- Horizon 2020
- National Institute on Handicapped Research
- Celgene
- AstraZeneca
- Genentech
- Novo Nordisk
- Merck
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K07-CA222159, F31-HD097958)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK105535, U01-DK085545)
- Howard Hughes Medical Institute
- Medical Research Council (MR/L020149/1)
- National Institute of General Medical Sciences (T32-GM007499)
- Boehringer Ingelheim
- Eli Lilly and Company
- Gilead Sciences
- Yale Cancer Center
- Stand Up To Cancer
- National Cancer Institute
- Chan Zuckerberg Initiative (CZF2019-002440)
- AbbVie
- National Institute for Health Research (NF-SI-0617-10090)
- European Commission
- Servier
- Sanofi
- Wellcome Trust (212259, 203141, 090532, 095101, 098381, 200837, 106130)
- TG Therapeutics
- Pfizer
- National Institutes of Health (U01-CA210171, P30-CA016359, P30-CA014051, DP2-CA248136)
- Takeda Pharmaceuticals U.S.A.
- Janssen Pharmaceuticals
- Roche
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- obesity, pancreatic ductal adenocarcinoma, cholecystokinin, pancreatic islet cells, pancreatic beta cells, KRAS oncogenic signaling, tumor microenvironment, carcinogenesis, weight loss, autochthonous mouse model, insulin
- MeSH terms
- Animals, Cell Line, Cell Transformation, Neoplastic, Disease Models, Animal, Exocrine Glands, Female, Humans, Male, Mice, Inbred C57BL, Mutation, Obesity, Pancreatic Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Disease Progression, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, Endocrine Cells, Tumor Microenvironment, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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