A Protumorigenic mDia2-MIRO1 Axis Controls Mitochondrial Positioning and Function in Cancer-Associated Fibroblasts.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
17 10 2022
17 10 2022
Historique:
received:
15
01
2022
revised:
02
06
2022
accepted:
09
08
2022
pubmed:
24
8
2022
medline:
19
10
2022
entrez:
23
8
2022
Statut:
ppublish
Résumé
Cancer-associated fibroblasts (CAF) are key regulators of tumorigenesis. Further insights into the tumor-promoting mechanisms of action of CAFs could help improve cancer diagnosis and treatment. Here we show that the formin mDia2 regulates the positioning and function of mitochondria in dermal fibroblasts, thereby promoting a protumorigenic CAF phenotype. Mechanistically, mDia2 stabilized the mitochondrial trafficking protein MIRO1. Loss of mDia2 or MIRO1 in fibroblasts or CAFs reduced the presence of mitochondria and ATP levels near the plasma membrane and at CAF-tumor cell contact sites, caused metabolic alterations characteristic of mitochondrial dysfunction, and suppressed the secretion of protumorigenic proteins. In mouse models of squamous carcinogenesis, genetic or pharmacologic inhibition of mDia2, MIRO1, or their common upstream regulator activin A inhibited tumor formation. Consistently, co-upregulation of mDia2 and MIRO1 in the stroma of various human cancers negatively correlated with survival. This work unveils a key role of mitochondria in the protumorigenic CAF phenotype and identifies an activin A-mDia2-MIRO1 signaling axis in CAFs with diagnostic and therapeutic potential. Inhibition of mDia2/MIRO1-mediated mitochondrial positioning in CAFs induces mitochondrial dysfunction and suppresses tumor growth, revealing a promising therapeutic strategy to target tumor-stroma cross-talk.
Identifiants
pubmed: 35997559
pii: 708292
doi: 10.1158/0008-5472.CAN-22-0162
pmc: PMC9574377
mid: EMS152980
doi:
Substances chimiques
Adenosine Triphosphate
8L70Q75FXE
Formins
0
Miro-1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3701-3717Subventions
Organisme : Swiss National Science Foundation
ID : 169204
Pays : Switzerland
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
Références
J Proteome Res. 2009 Aug;8(8):4135-43
pubmed: 19469553
Trends Mol Med. 2020 Dec;26(12):1107-1117
pubmed: 32878730
Nucleic Acids Res. 2019 Jul 2;47(W1):W556-W560
pubmed: 31114875
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Cancer Res. 2004 Feb 1;64(3):985-93
pubmed: 14871829
Nucleic Acids Res. 2013 Jan;41(Database issue):D991-5
pubmed: 23193258
Cell Res. 2018 Mar;28(3):265-280
pubmed: 29219147
Sci Rep. 2015 Apr 30;5:9802
pubmed: 25925024
Nat Rev Cancer. 2020 Mar;20(3):174-186
pubmed: 31980749
BMC Gastroenterol. 2020 Dec 9;20(1):411
pubmed: 33297976
Free Radic Biol Med. 2015 Dec;89:322-32
pubmed: 26427885
Cell Commun Signal. 2020 Apr 7;18(1):59
pubmed: 32264958
Nature. 2021 Mar;591(7851):659-664
pubmed: 33658713
Nat Commun. 2019 Feb 12;10(1):711
pubmed: 30755613
J Neurosci. 2015 Dec 2;35(48):15996-6011
pubmed: 26631479
Dev Cell. 2018 Jul 16;46(2):145-161.e10
pubmed: 30016619
Mol Cell Proteomics. 2015 Apr;14(4):1064-78
pubmed: 25682332
J Cell Sci. 2021 Apr 15;134(8):
pubmed: 33722978
Biomed Res Int. 2018 Jun 5;2018:6075403
pubmed: 29967776
J Cell Biol. 2018 Feb 5;217(2):619-633
pubmed: 29222186
Oncol Rep. 2020 Oct;44(4):1671-1685
pubmed: 32945508
Am J Cancer Res. 2015 Mar 15;5(4):1460-70
pubmed: 26101710
Life Sci Alliance. 2021 Jan 27;4(3):
pubmed: 33504622
Cell Adh Migr. 2018;12(5):401-416
pubmed: 29513145
EMBO J. 2020 Apr 15;39(8):e103334
pubmed: 32134147
Cell. 2011 Nov 11;147(4):893-906
pubmed: 22078885
Nat Commun. 2020 May 25;11(1):2604
pubmed: 32451392
J Vis Exp. 2011 May 06;(51):
pubmed: 21587162
EMBO J. 2008 Mar 19;27(6):886-97
pubmed: 18288204
J Clin Bioinforma. 2013 Oct 28;3(1):22
pubmed: 24165311
Front Endocrinol (Lausanne). 2020 May 22;11:319
pubmed: 32528413
J Cell Sci. 2021 May 15;134(10):
pubmed: 34013964
J Proteome Res. 2016 Dec 2;15(12):4624-4637
pubmed: 27769112
Cell Metab. 2019 Dec 3;30(6):1131-1140.e7
pubmed: 31564441
Acta Histochem. 2017 Apr;119(3):315-326
pubmed: 28314612
Nat Commun. 2018 Jul 11;9(1):2682
pubmed: 29992963
Mol Biol Cell. 2017 Aug 1;28(16):2159-2169
pubmed: 28615318
EMBO Rep. 2020 Nov 5;21(11):e50078
pubmed: 32909687
Mol Pharmacol. 2002 Jul;62(1):65-74
pubmed: 12065756
Biochem Soc Trans. 2016 Dec 15;44(6):1701-1708
pubmed: 27913680
Cancer Cell. 2011 Aug 16;20(2):229-45
pubmed: 21840487
Nat Cell Biol. 2008 Jul;10(7):849-57
pubmed: 18516090
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
PLoS Genet. 2016 Oct 7;12(10):e1006359
pubmed: 27716788
Cytokine Growth Factor Rev. 2021 Aug;60:1-17
pubmed: 33933900
J Cell Sci. 2014 Dec 1;127(Pt 23):5105-14
pubmed: 25300794
Nat Rev Cancer. 2021 Apr;21(4):217-238
pubmed: 33589810
Autophagy. 2018;14(9):1644-1645
pubmed: 30058425
Neuron. 2005 Aug 4;47(3):365-78
pubmed: 16055061
Nat Methods. 2021 Nov;18(11):1294-1303
pubmed: 34725485
EMBO Mol Med. 2020 Apr 7;12(4):e11466
pubmed: 32150356
EMBO J. 2018 Feb 1;37(3):321-336
pubmed: 29311115
Nat Cell Biol. 2015 Sep;17(9):1193-204
pubmed: 26302407
Sci Transl Med. 2018 May 9;10(440):
pubmed: 29743348
Nucleic Acids Res. 2020 Jul 2;48(W1):W509-W514
pubmed: 32442275
Small GTPases. 2014;5:
pubmed: 24911990
Methods Mol Biol. 2011;731:151-9
pubmed: 21516406