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

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; Rafael Kramann; Alex Von Kriegsheim; Vincent Gnanapragasam; Anne Y Warren; Grant D Stewart; Ayelet Erez; Sakari Vanharanta; Julio Saez-Rodriguez; Christian Frezza

doi:10.1038/s41467-022-35036-4

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

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, Rafael KramannAlex Von Kriegsheim, Vincent Gnanapragasam, Anne Y Warren, Grant D Stewart, Ayelet Erez, Sakari Vanharanta, Julio Saez-Rodriguez^*, Christian Frezza^*

^*Corresponding author for this work

Department of Molecular Cell Biology

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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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.

Original language	English
Article number	7830
Number of pages	20
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35036-4
Publication status	Published - Dec 2022

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Sciacovelli, M., Dugourd, A., Jimenez, L. V., Yang, M., Nikitopoulou, E., Costa, A. S. H., Tronci, L., Caraffini, V., Rodrigues, P., Schmidt, C., Ryan, D. G., Young, T., Zecchini, V. R., Rossi, S. H., Massie, C., Lohoff, C., Masid, M., Hatzimanikatis, V., Kuppe, C., ... Frezza, C. (2022). Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression. Nature Communications, 13(1), Article 7830. https://doi.org/10.1038/s41467-022-35036-4

@article{016e00567f4147fe9982135a88737235,

title = "Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression",

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.",

author = "Marco Sciacovelli and Aurelien Dugourd and Jimenez, {Lorea Valcarcel} and Ming Yang and Efterpi Nikitopoulou and Costa, {Ana S H} and Laura Tronci and Veronica Caraffini and Paulo Rodrigues and Christina Schmidt and Ryan, {Dylan Gerard} and Timothy Young and Zecchini, {Vincent R} and Rossi, {Sabrina H} and Charlie Massie and Caroline Lohoff and Maria Masid and Vassily Hatzimanikatis and Christoph Kuppe and Rafael Kramann and {Von Kriegsheim}, Alex and Vincent Gnanapragasam and Warren, {Anne Y} and Stewart, {Grant D} and Ayelet Erez and Sakari Vanharanta and Julio Saez-Rodriguez and Christian Frezza",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-35036-4",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

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Sciacovelli, M, Dugourd, A, Jimenez, LV, Yang, M, Nikitopoulou, E, Costa, ASH, Tronci, L, Caraffini, V, Rodrigues, P, Schmidt, C, Ryan, DG, Young, T, Zecchini, VR, Rossi, SH, Massie, C, Lohoff, C, Masid, M, Hatzimanikatis, V, Kuppe, C, Kramann, R, Von Kriegsheim, A, Gnanapragasam, V, Warren, AY, Stewart, GD, Erez, A, Vanharanta, S, Saez-Rodriguez, J & Frezza, C 2022, 'Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression', Nature Communications, vol. 13, no. 1, 7830. https://doi.org/10.1038/s41467-022-35036-4

TY - JOUR

T1 - Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression

AU - Sciacovelli, Marco

AU - Dugourd, Aurelien

AU - Jimenez, Lorea Valcarcel

AU - Yang, Ming

AU - Nikitopoulou, Efterpi

AU - Costa, Ana S H

AU - Tronci, Laura

AU - Caraffini, Veronica

AU - Rodrigues, Paulo

AU - Schmidt, Christina

AU - Ryan, Dylan Gerard

AU - Young, Timothy

AU - Zecchini, Vincent R

AU - Rossi, Sabrina H

AU - Massie, Charlie

AU - Lohoff, Caroline

AU - Masid, Maria

AU - Hatzimanikatis, Vassily

AU - Kuppe, Christoph

AU - Kramann, Rafael

AU - Von Kriegsheim, Alex

AU - Gnanapragasam, Vincent

AU - Warren, Anne Y

AU - Stewart, Grant D

AU - Erez, Ayelet

AU - Vanharanta, Sakari

AU - Saez-Rodriguez, Julio

AU - Frezza, Christian

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-022-35036-4

DO - 10.1038/s41467-022-35036-4

M3 - Article

C2 - 36539415

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7830

ER -

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

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