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.
Nature communications. 2022 Dec 20*** epublish ***
Marco Sciacovelli, Aurelien Dugourd, Lorea Valcarcel Jimenez, Ming Yang, Efterpi Nikitopoulou, Ana S H Costa, Laura Tronci, Veronica Caraffini, Paulo Rodrigues, Christina Schmidt, Dylan Gerard Ryan, Timothy Young, Vincent R Zecchini, Sabrina H Rossi, Charlie Massie, Caroline Lohoff, Maria Masid, Vassily Hatzimanikatis, Christoph Kuppe, Alex Von Kriegsheim, Rafael Kramann, Vincent Gnanapragasam, Anne Y Warren, Grant D Stewart, Ayelet Erez, Sakari Vanharanta, Julio Saez-Rodriguez, Christian Frezza
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany., Early Detection Programme, CRUK Cambridge Centre, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland., Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany., Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, Crewe Road South, Edinburgh, EH4 2XR, UK., Department of Surgery, University of Cambridge and Cambridge University Hospitals NHS Cambridge Biomedical Campus, Cambridge, UK., Department of Histopathology-Cambridge University Hospitals NHS, Box 235 Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK., Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany. ., Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK. .