Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression.

Autor: Sciacovelli M; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK.; Department of Molecular and Clinical Cancer Medicine; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3GE, UK., Dugourd A; Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany.; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany., Jimenez LV; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK.; CECAD Research Center, Faculty of Medicine-University Hospital Cologne, 50931, Cologne, Germany., Yang M; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK.; CECAD Research Center, Faculty of Medicine-University Hospital Cologne, 50931, Cologne, Germany., Nikitopoulou E; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Costa ASH; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK.; Matterworks, Somerville, MA, 02143, USA., Tronci L; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Caraffini V; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Rodrigues P; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Schmidt C; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK.; CECAD Research Center, Faculty of Medicine-University Hospital Cologne, 50931, Cologne, Germany., Ryan DG; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Young T; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Zecchini VR; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Rossi SH; Early Detection Programme, CRUK Cambridge Centre, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Massie C; Early Detection Programme, CRUK Cambridge Centre, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK., Lohoff C; Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany., Masid M; Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.; Ludwig Institute for Cancer Research, Department of Oncology, Lausanne University Hospital (CHUV), University of Lausanne, CH-1011, Lausanne, Switzerland., Hatzimanikatis V; Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland., Kuppe C; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.; Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany., Von Kriegsheim A; Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, Crewe Road South, Edinburgh, EH4 2XR, UK., Kramann R; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.; Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands., Gnanapragasam V; Department of Surgery, University of Cambridge and Cambridge University Hospitals NHS Cambridge Biomedical Campus, Cambridge, UK., Warren AY; Department of Histopathology-Cambridge University Hospitals NHS, Box 235 Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK., Stewart GD; Department of Surgery, University of Cambridge and Cambridge University Hospitals NHS Cambridge Biomedical Campus, Cambridge, UK., Erez A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Vanharanta S; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK.; Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Saez-Rodriguez J; Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany. pub.saez@uni-heidelberg.de., Frezza C; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197 Biomedical Campus, Cambridge, CB2 0XZ, UK. christian.frezza@uni-koeln.de.; CECAD Research Center, Faculty of Medicine-University Hospital Cologne, 50931, Cologne, Germany. christian.frezza@uni-koeln.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Dec 20; Vol. 13 (1), pp. 7830. Date of Electronic Publication: 2022 Dec 20.
DOI: 10.1038/s41467-022-35036-4
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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