We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression.
- Authors
Sciacovelli, Marco; Dugourd, Aurelien; Jimenez, Lorea Valcarcel; Yang, Ming; Nikitopoulou, Efterpi; Costa, Ana S. H.; Tronci, Laura; Caraffini, Veronica; Rodrigues, Paulo; Schmidt, Christina; Ryan, Dylan Gerard; Young, Timothy; Zecchini, Vincent R.; Rossi, Sabrina H.; Massie, Charlie; Lohoff, Caroline; Masid, Maria; Hatzimanikatis, Vassily; Kuppe, Christoph; Von Kriegsheim, Alex
- Abstract
Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies. Primary and metastatic tumours have different metabolic phenotypes due to changes in nutrient availability. Here the authors perform multi-omic analyses of primary and metastatic renal cancer cells grown in a physiological medium and show that the reprogramming of the branched-chain amino acid catabolism and urea cycle through re-expression of ASS1 allows metabolic flexibility during renal cancer progression.
- Subjects
RENAL cancer; CANCER invasiveness; METASTASIS; CANCER cells; PHENOTYPIC plasticity; AMINO acid analysis; CITRULLINE
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-35036-4