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Science. 2016 Sep 9;353(6304):1161-5. doi: 10.1126/science.aaf5171.

Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers.

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. These authors contributed equally to this work.
2
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Center for Computational Biology and Bioinformatics and Department of Systems Biology, Columbia University, New York, NY 10027, USA.
5
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA. Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
6
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
8
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA. Dana-Farber Cancer Institute, Boston, MA 02115, USA. mvh@mit.edu.

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.

PMID:
27609895
PMCID:
PMC5245791
DOI:
10.1126/science.aaf5171
[Indexed for MEDLINE]
Free PMC Article

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