Sciacovelli, Marco, Dugourd, Aurelien, Jimenez, Lorea Valcarcel, Yang, Ming ORCID: 0000-0002-7735-7804, Nikitopoulou, Efterpi, Costa, Ana S. H., Tronci, Laura, Caraffini, Veronica, Rodrigues, Paulo, Schmidt, Christina ORCID: 0000-0002-3867-0881, Ryan, Dylan Gerard, Young, Timothy, Zecchini, Vincent R., Rossi, Sabrina H., Massie, Charlie, Lohoff, Caroline ORCID: 0000-0002-3084-8833, Masid, Maria, Hatzimanikatis, Vassily, Kuppe, Christoph, Von Kriegsheim, Alex, Kramann, Rafael, Gnanapragasam, Vincent, Warren, Anne Y., Stewart, Grant D., Erez, Ayelet, Vanharanta, Sakari, Saez-Rodriguez, Julio ORCID: 0000-0002-8552-8976 and Frezza, Christian (2022). Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression. Nat. Commun., 13 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Sciacovelli, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dugourd, AurelienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jimenez, Lorea ValcarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, MingUNSPECIFIEDorcid.org/0000-0002-7735-7804UNSPECIFIED
Nikitopoulou, EfterpiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Costa, Ana S. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tronci, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caraffini, VeronicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodrigues, PauloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ChristinaUNSPECIFIEDorcid.org/0000-0002-3867-0881UNSPECIFIED
Ryan, Dylan GerardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, TimothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zecchini, Vincent R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossi, Sabrina H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Massie, CharlieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohoff, CarolineUNSPECIFIEDorcid.org/0000-0002-3084-8833UNSPECIFIED
Masid, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hatzimanikatis, VassilyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuppe, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Von Kriegsheim, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kramann, RafaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gnanapragasam, VincentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warren, Anne Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stewart, Grant D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erez, AyeletUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vanharanta, SakariUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saez-Rodriguez, JulioUNSPECIFIEDorcid.org/0000-0002-8552-8976UNSPECIFIED
Frezza, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-693136
DOI: 10.1038/s41467-022-35036-4
Journal or Publication Title: Nat. Commun.
Volume: 13
Number: 1
Date: 2022
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
REDUCTIVE CARBOXYLATION; ARGININE DEPRIVATION; METABOLISM; ASPARTATE; HALLMARKS; CELLS; BIOSYNTHESIS; METASTASIS; GLUTAMINE; FUMARATEMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69313

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