Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras -driven cancers
| Autor: | Brian W. Ji, Alexander Muir, Margaret E. Torrence, Matthew R. Bauer, Allison N. Lau, Brian M. Wolpin, Aaron M. Hosios, Matthew G. Vander Heiden, Thales Papagiannakopoulos, Dennis Vitkup, Purushottam D. Dixit, Laura V. Danai, Christopher R. Chin, Elizaveta Freinkman, Tyler Jacks, Jared R. Mayers, Shawn M. Davidson |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Mayers, Jared R., Torrence, Margaret E., Danai, Laura V., Papagiannakopoulos, Thales, Davidson, Shawn M., Bauer, Matthew R., Lau, Allison N., Hosios, Aaron Marc, Muir, Alexander, Chin, Christopher R., Freinkman, Elizaveta, Jacks, Tyler E., Vander Heiden, Matthew G. |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Multidisciplinary Branched-chain amino acid Cell Cancer Context (language use) Biology medicine.disease_cause medicine.disease 03 medical and health sciences chemistry.chemical_compound Metabolic pathway 030104 developmental biology medicine.anatomical_structure Biochemistry chemistry Cell culture medicine Cancer research KRAS Pancreas |
| Zdroj: | PMC |
| ISSN: | 1095-9203 0036-8075 |
| DOI: | 10.1126/science.aaf5171 |
| Popis: | 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. National Institutes of Health (U.S.) (Grant F30CA183474) National Institutes of Health (U.S.) (Grant T32GM007753) |
| Databáze: | OpenAIRE |
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