Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers
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Author(s)
Ji, B. W.
Dixit, P. D.
Wolpin, B. M.
Vitkup, D.
Mayers, Jared R.
Torrence, Margaret E.
Danai, Laura V.
Papagiannakopoulos, Thales
Davidson, Shawn M.
Bauer, Matthew R.
Date Issued
September 2016
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Mayers, J. R. et al. “Tissue of Origin Dictates Branched-Chain Amino Acid Metabolism in Mutant Kras-Driven Cancers.” Science 353, 6304 (September 2016): 1161–1165 © 2016 American Association for the Advancement of Science
Version
Author's final manuscript
Abstract
Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific metabolic pathways is unknown. Kras activation and Trp53 deletion in the pancreas or the lung result in pancreatic ductal adenocarinoma (PDAC) or non-small cell lung carcinoma (NSCLC), respectively, but despite the same initiating events, these tumors use branched-chain amino acids (BCAAs) differently. NSCLC tumors incorporate free BCAAs into tissue protein and use BCAAs as a nitrogen source, whereas PDAC tumors have decreased BCAA uptake. These differences are reflected in expression levels of BCAA catabolic enzymes in both mice and humans. Loss of Bcat1 and Bcat2, the enzymes responsible for BCAA use, impairs NSCLC tumor formation, but these enzymes are not required for PDAC tumor formation, arguing that tissue of origin is an important determinant of how cancers satisfy their metabolic requirements.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/SCIENCE.AAF5171
