Elevated circulating branched chain amino acids are an early event in pancreatic adenocarcinoma development
Name
Vander Heiden_Elevation of.pdf
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Author(s)
Mayers, Jared R.
Torrence, Margaret E.
Fiske, Brian Prescott
Davidson, Shawn Michael
Papagiannakopoulos, Thales
Dayton, Talya Lucia
Vander Heiden, Matthew G.
Alternative Title
Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development
Date Issued
September 2014
Journal
Nature Medicine
Publisher
Nature Publishing Group
Citation
Mayers, Jared R, Chen Wu, Clary B Clish, Peter Kraft, Margaret E Torrence, Brian P Fiske, Chen Yuan, et al. “Elevation of Circulating Branched-Chain Amino Acids Is an Early Event in Human Pancreatic Adenocarcinoma Development.” Nature Medicine 20, no. 10 (September 28, 2014): 1193–1198.
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Author's final manuscript
Abstract
Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/nm.3686
