Nitrogen partitioning between branched-chain amino acids and urea cycle enzymes sustains renal cancer progression

SUMMARYMetabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we combined multi-omics datasets of primary and metastatic clonally related clear cell renal cancer cells (ccRCC) and generated a computational tool to explore the metabolic landscape during cancer progression. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism is required to maintain the aspartate pool in cancer cells across all tumor stages. We also provide evidence that metastatic renal cancer cells reactivate argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, to enable invasion in vitro and metastasis in vivo. Overall, our study provides the first comprehensive elucidation of the molecular mechanisms responsible for metabolic flexibility in ccRCC, paving the way to the development of therapeutic strategies based on the specific metabolism that characterizes each tumor stage.HighlightsBranched-chain amino acids catabolism is reprogrammed in ccRCC tumorsBCAT-dependent transamination supplies nitrogen for de novo biosynthesis of amino acids including aspartate and asparagine in ccRCCAspartate produced downstream of BCAT is used specifically by metastatic cells through argininosuccinate synthase (ASS1) and argininosuccinate lyase (ASL) to generate arginine, providing a survival advantage in the presence of microenvironments with rate limiting levels of arginineASS1 is re-expressed in metastatic 786-M1A through epigenetic remodeling and it is sensitive to arginine levelsSilencing of ASS1 impairs the metastatic potential in vitro and in vivo of ccRCC cells