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

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 utilize branched-chain amino acids (BCAAs) differently. NSCLC tumors incorporate free BCAAs into tissue protein and use BCAAs as a nitrogen source while 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 utilization, 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.

The General Explanation Method with NMR Spectroscopy Enables the Identification of Metabolite Profiles Specific for Normal and Tumor Cell Lines

“…Valine and isoleucine are together with leucine collectively known as the branched‐chain amino acids (BCAAs), whereas NAD is one of the five coenzymes involved in the formation of branched‐chain α‐keto acids (BCKAs). The metabolic concentration profile of the A549 cell line is in accordance with the current understanding of the metabolism of the non‐small lung carcinoma (NSCLC) cells, for which overexpression of branched‐chain aminotransferase 1 (BCAT1) results in increased intracellular concentrations of BCAAs through the amination of BCKAs 17, 18, 19. In support, both glutamic acid and glutathione have active roles in the proliferation processes of the A549 cell line, and an increased concentration of glutathione has also been observed in tumor A549 cells 20, 21.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…These above ref er enced stud ies sug gest that the tu mor en vi ron ment is at least as im por tant as the ge net ics of a tu mor for pre dict ing its meta bolic pro file [252][253][254]. An other re cent study also points at the tis sue of ori gin as a ma jor dri ver of the meta bolic be hav ior of a tu mor [268]. May ers et al [268] in deed used a mouse model with Kras ac ti va tion and Tr p53 dele tion in the pan creas or in the lungs to gen er ate spon ta neous PDAC and NSCLC, re spec tively.…”

“…An other re cent study also points at the tis sue of ori gin as a ma jor dri ver of the meta bolic be hav ior of a tu mor [268]. May ers et al [268] in deed used a mouse model with Kras ac ti va tion and Tr p53 dele tion in the pan creas or in the lungs to gen er ate spon ta neous PDAC and NSCLC, re spec tively. Al though both tu mor mod els shared the same ini ti at ing mu ta tions, au thors ob served ma jor dif fer ences in branched chain amino acid (BCAA) me tab o lism: NSCLC, but not PDAC, had high BCAA up take and con tained high lev els of BCAA de rived pro teins [268,269].…”

“…Al though both tu mor mod els shared the same ini ti at ing mu ta tions, au thors ob served ma jor dif fer ences in branched chain amino acid (BCAA) me tab o lism: NSCLC, but not PDAC, had high BCAA up take and con tained high lev els of BCAA de rived pro teins [268,269]. Fur ther ex per i ments demon strated that NSCLC rely on BCAA as a main ni tro gen source [268,269]. Ge netic dele tion of Bcat1 and Bcat2, which en code the two iso forms of BCAA transam i nase, sig nif i cantly im paired NSCLC tu mor for ma tion but did not af fect PDAC tu mor growth.…”

“…May ers et al [268] in deed used a mouse model with Kras ac ti va tion and Tr p53 dele tion in the pan creas or in the lungs to gen er ate spon ta neous PDAC and NSCLC, re spec tively. Al though both tu mor mod els shared the same ini ti at ing mu ta tions, au thors ob served ma jor dif fer ences in branched chain amino acid (BCAA) me tab o lism: NSCLC, but not PDAC, had high BCAA up take and con tained high lev els of BCAA de rived pro teins [268,269]. Fur ther ex per i ments demon strated that NSCLC rely on BCAA as a main ni tro gen source [268,269].…”