Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 12 2022
20 12 2022
Historique:
received:
20
10
2021
accepted:
16
11
2022
entrez:
20
12
2022
pubmed:
21
12
2022
medline:
23
12
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36539415
doi: 10.1038/s41467-022-35036-4
pii: 10.1038/s41467-022-35036-4
pmc: PMC9767928
doi:
Substances chimiques
Amino Acids, Branched-Chain
0
Nitrogen
N762921K75
Arginine
94ZLA3W45F
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7830Subventions
Organisme : Medical Research Council
ID : MC_UU_12022/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MRC_MC_UU_12022/6
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C51061/A27453
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12022/7
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1101/4
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
Références
Nat Commun. 2019 Aug 20;10(1):3739
pubmed: 31431624
Cell. 2015 Jul 30;162(3):540-51
pubmed: 26232224
Cell Rep. 2015 Jul 7;12(1):116-127
pubmed: 26119730
J Clin Invest. 2017 May 1;127(5):1631-1645
pubmed: 28346230
Science. 2016 Sep 9;353(6304):1161-5
pubmed: 27609895
Mol Cell. 2012 Dec 14;48(5):681-91
pubmed: 23103253
Sci Adv. 2019 Jan 02;5(1):eaau7314
pubmed: 30613774
Int J Cancer. 2010 Jun 15;126(12):2762-72
pubmed: 20104527
Mol Syst Biol. 2021 Jan;17(1):e9730
pubmed: 33502086
Tumour Biol. 2014 Jan;35(1):161-9
pubmed: 23897555
Int J Cancer. 2009 Sep 15;125(6):1454-63
pubmed: 19533750
Sci Rep. 2020 Apr 6;10(1):5955
pubmed: 32249812
Bioinformatics. 2019 Jan 1;35(1):167-169
pubmed: 30561545
Cell Metab. 2016 Jan 12;23(1):27-47
pubmed: 26771115
Cancer Discov. 2020 Dec;10(12):1797-1807
pubmed: 33139243
Nat Rev Nephrol. 2017 Jul;13(7):410-419
pubmed: 28480903
Cancer Cell. 2016 Jan 11;29(1):104-116
pubmed: 26766592
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Cancer Res. 2019 Dec 15;79(24):6153-6165
pubmed: 31594836
Nature. 2014 Sep 11;513(7517):251-5
pubmed: 25043030
Nature. 2017 Nov 16;551(7680):384-388
pubmed: 29144447
Dis Model Mech. 2018 May 3;11(8):
pubmed: 29739810
Nat Rev Cancer. 2021 Mar;21(3):162-180
pubmed: 33462499
Cell. 2017 Feb 9;168(4):657-669
pubmed: 28187287
Cell Death Dis. 2013 Jan 17;4:e458
pubmed: 23328665
Clin Cancer Res. 2013 Jun 1;19(11):2861-72
pubmed: 23549872
Nat Cell Biol. 2018 Jul;20(7):775-781
pubmed: 29941933
Nat Commun. 2016 Oct 10;7:13041
pubmed: 27721378
Elife. 2019 Apr 16;8:
pubmed: 30990168
Nat Commun. 2020 Jun 4;11(1):2821
pubmed: 32499584
Nature. 2015 Nov 19;527(7578):379-383
pubmed: 26560030
Cell Metab. 2019 Feb 5;29(2):417-429.e4
pubmed: 30449684
Dis Model Mech. 2018 Aug 6;11(8):
pubmed: 30082427
Cancer Cell. 2020 Feb 10;37(2):147-156
pubmed: 32049045
Cell Metab. 2018 Jun 05;27(6):1263-1280.e6
pubmed: 29754953
Cell. 2017 Apr 06;169(2):258-272.e17
pubmed: 28388410
Cell Rep. 2018 Jun 19;23(12):3698
pubmed: 29925010
Mol Cell Oncol. 2019 Jul 9;6(5):e1536843
pubmed: 31528687
Nat Biotechnol. 2013 May;31(5):419-25
pubmed: 23455439
Metab Eng. 2018 Jan;45:149-157
pubmed: 29191787
Nature. 2016 Aug 31;537(7621):544-547
pubmed: 27580029
Mol Metab. 2020 Mar;33:83-101
pubmed: 31668988
Cell. 2019 Oct 31;179(4):964-983.e31
pubmed: 31675502
Mol Cell. 2018 Feb 15;69(4):581-593.e7
pubmed: 29452638
Cell. 2018 Sep 20;175(1):101-116.e25
pubmed: 30220459
Nat Cell Biol. 2016 Jun;18(6):645-656
pubmed: 27214280
Nature. 2013 Jul 4;499(7456):43-9
pubmed: 23792563
Methods Mol Biol. 2014;1191:49-63
pubmed: 25178783
FEBS Open Bio. 2019 Jan 07;9(2):241-247
pubmed: 30761250
Nature. 2011 Nov 20;481(7381):385-8
pubmed: 22101431
Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):E866-75
pubmed: 24550497
Nat Rev Cancer. 2018 Oct;18(10):634-645
pubmed: 30194362
Nat Med. 2013 Jan;19(1):50-6
pubmed: 23223005
Elife. 2021 Dec 23;10:
pubmed: 34939929
Nat Chem Biol. 2018 Nov;14(11):1021-1031
pubmed: 30327559
N Engl J Med. 2017 Jan 26;376(4):354-366
pubmed: 28121507
Cancer Discov. 2018 Jul;8(7):850-865
pubmed: 29875134
Nat Rev Drug Discov. 2022 Apr;21(4):283-305
pubmed: 35031766
BMC Cancer. 2014 Aug 28;14:621
pubmed: 25164070
Trends Cell Biol. 2018 Aug;28(8):673-684
pubmed: 29747903
Cell. 2015 Jul 30;162(3):552-63
pubmed: 26232225
Cancer Res. 2014 Feb 1;74(3):896-907
pubmed: 24285724
Methods Mol Biol. 2016;1386:253-81
pubmed: 26677187
Cell Mol Life Sci. 2021 Jan;78(1):195-206
pubmed: 32088728
Science. 2018 Aug 10;361(6402):594-599
pubmed: 30093597
Annu Rev Physiol. 2019 Feb 10;81:139-164
pubmed: 30485760
Cell Rep. 2017 Jan 24;18(4):991-1004
pubmed: 28122247