Altered exocrine function can drive adipose wasting in early pancreatic cancer
Open accessAbstract
Malignancy is accompanied by changes in the metabolism of both cells and the organism 1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer 3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic 5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.
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Exocrine insufficiency appears to contribute to weight loss in pancreatic ductal adenocarcinoma.
“and exocrine insufficiency appears to be a contributing cause.116”
From Early detection of pancreatic cancer (2020) · cites this paper as [116]
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Self-citation
- Authors
- Danai, L. V., Babic, A., Rosenthal, M. H., Dennstedt, E. A., Muir, A., Lien, E. C., Mayers, J. R., Tai, K., Lau, A. N., Jones-Sali, P., Prado, C. M., Petersen, G. M., Takahashi, N., Sugimoto, M., Yeh, J. J., Lopez, N., Bardeesy, N., Fernandez-del Castillo, C., Liss, A. S., Koong, A. C., Bui, J., Yuan, C., Welch, M. W., Brais, L. K., Kulke, M. H., Dennis, C., Clish, C. B., Wolpin, B. M., & Vander Heiden, M. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Dana-Farber Cancer Institute (US)
- University of Alberta (CA)
- Mayo Clinic (US)
- University of North Carolina at Chapel Hill (US)
- University of California San Diego (US)
- Harvard University (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, Los Angeles (US)
- Boston University (US)
- Broad Institute (US)
- Corresponding author
- Wolpin, Brian M.
- ORCID
- Danai, Laura V.
- Rosenthal, Michael H.
- Muir, Alexander
- Lien, Evan C.
- Mayers, Jared R.
- Tai, Karen
- Lau, Allison N.
- Prado, Carla M.
- Petersen, Gloria M.
- Takahashi, Naoki
- Sugimoto, Motokazu
- Yeh, Jen Jen
- Lopez, Nicole
- Bardeesy, Nabeel
- Liss, Andrew S.
- Koong, Albert C.
- Bui, Justin
- Yuan, Chen
- Brais, Lauren K.
- Kulke, Matthew H.
- Dennis, Courtney
- Clish, Clary B.
- Wolpin, Brian M.
- Venue
- Nature
- Published
- 2018-06
- Volume
- 558
- Issue
- 7711
- Pages
- 600-604
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6112987
- OpenAlex
- W2809397712
- Cited by
- 141
- References
- 33
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 18 · 2023: 12 · 2022: 16 · 2021: 21 · 2020: 20 · 2019: 24 · 2018: 10 · 2017: 1
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Defense (CA130288)
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation (DRG‐2299‐17, DRG-2241-15)
- Pancreatic Cancer Action Network
- Lustgarten Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Institutes of Health (CA130288)
- Stand Up To Cancer
- Ludwig Center for Molecular Oncology
- Ludwig Center at Harvard
- National Cancer Institute (P50CA127003, CA130288, F32CA210421, F32CA213810, R01CA168653, P50CA102701, K07CA222159, P30CA014051, P01CA117969, U01CA210171, P30-CA-14051)
- National Institute of General Medical Sciences (T32GM007287)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, cancer cachexia, adipose tissue wasting, skeletal muscle atrophy, pancreatic exocrine function, pancreatic enzymes, tumor microenvironment, tumor growth, survival
- MeSH terms
- Adipose Tissue, Animals, Body Composition, Disease Models, Animal, Female, Male, Exocrine Pancreatic Insufficiency, Pancreatic Neoplasms, Disease Progression, Mice
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