Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras -driven cancers
Open accessAbstract
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.
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Lung tumors support their nitrogen requirement by catabolizing free branched chain amino acids, whereas pancreatic tumors expressing the same driver mutation do not.
“Lung tumors support their nitrogen requirement by catabolizing free branched chain amino acids (BCAA), whereas pancreatic tumors expressing the same driver mutation do not.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Mayers et al., 2016
Mouse lung and pancreatic tumors exhibit differences in amino acid metabolism even when they harbor the same genetic lesion.
“Recently, it has been determined that mouse lung and pancreatic tumors exhibit differences in amino acid metabolism, even when harboring the same genetic lesion.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Mayers et al., 2016
Targeting BCAA transaminases inhibits lung tumor formation better than pancreatic tumor formation, suggesting that dependence on BCAA catabolism is determined by cell lineage rather than tumor site.
“Targeting BCAA transaminases inhibits lung tumor formation better than pancreatic tumor formation, suggesting that dependence on branched chain amino acid catabolism is determined by cell lineage rather than tumor site (Mayers et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Mayers et al., 2016
The tissue of origin dictates dependency on BCAA catabolism in normal physiology and in cancer.
“The tissue of origin dictates dependency on BCAA catabolism in normal physiology and in cancer.45”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [45]
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- Authors
- Mayers, J. R., Torrence, M. E., Danai, L. V., Papagiannakopoulos, T., Davidson, S. M., Bauer, M. R., Lau, A. N., Ji, B. W., Dixit, P. D., Hosios, A. M., Muir, A., Chin, C. R., Freinkman, E., Jacks, T., Wolpin, B. M., Vitkup, D., & Vander Heiden, M. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Columbia University (US)
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Dana-Farber Cancer Institute (US)
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
- ORCID
- Venue
- Science
- Published
- 2016-09-09
- Volume
- 353
- Issue
- 6304
- Pages
- 1161-1165
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5245791
- OpenAlex
- W2513280988
- Cited by
- 582
- References
- 51
- Citations by year
- 2026: 35 · 2025: 53 · 2024: 52 · 2023: 56 · 2022: 64 · 2021: 90 · 2020: 59 · 2019: 58 · 2018: 55 · 2017: 51 · 2016: 7
- FWCI
- 23.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- NIH National Cancer Institute (NCI) (F30CA183474)
- National Institute of General Medical Sciences (T32GM007753)
- Damon Runyon Cancer Research Foundation (DRG-2241-15)
- NCI (P30CA1405141, R01CA168653, R01CA201276)
- Burroughs Wellcome Fund
- Eisen and Chang Families
- Ludwig Center at Massachusetts Institute of Technology
- Stand Up To Cancer
- Lustgarten Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- branched-chain amino acids, KRAS mutation, Trp53 deletion, pancreatic ductal adenocarcinoma, non-small cell lung cancer, tissue of origin, cancer metabolism, BCAA catabolism, BCAT1, BCAT2, amino acid uptake, nitrogen source
- MeSH terms
- Amino Acids, Branched-Chain, Transaminases, Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Male, Mice, Inbred C57BL, Mutation, Nitrogen, Organ Specificity, Pancreatic Neoplasms, Pregnancy Proteins, Minor Histocompatibility Antigens, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Carcinoma, Pancreatic Ductal, Mice, Metabolic Networks and Pathways
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.
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