Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers.
Authors | |
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. |
Year of Publication | 2016
|
Journal | Science
|
Volume | 353
|
Issue | 6304
|
Pages | 1161-5
|
Date Published | 2016 09 09
|
ISSN | 1095-9203
|
DOI | 10.1126/science.aaf5171
|
PubMed ID | 27609895
|
PubMed Central ID | PMC5245791
|
Links | |
Grant list | F30 CA183474 / CA / NCI NIH HHS / United States
R01 CA168653 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 CA201276 / CA / NCI NIH HHS / United States
|