Phosphoinositide Conversion Inactivates R-RAS and Drives Metastases in Breast Cancer.
PI3KC2α
R-RAS
RASA3
breast cancer
focal adhesions
metastases
migration
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
revised:
03
11
2021
received:
28
07
2021
pubmed:
1
2
2022
medline:
8
4
2022
entrez:
31
1
2022
Statut:
ppublish
Résumé
Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R-RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof-of-concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α-overexpressing breast cancer, thereby suggesting a novel strategy for anti-breast cancer therapy.
Identifiants
pubmed: 35098698
doi: 10.1002/advs.202103249
pmc: PMC8948670
doi:
Substances chimiques
GTPase-Activating Proteins
0
Phosphatidylinositols
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2103249Subventions
Organisme : Associazione Italiana Ricerca Cancro
ID : (20177E9EPY
Organisme : Fondazione Ricerca Molinette
Organisme : Fondazione Pezcoller-SIC "Patrizia Coser"
Organisme : Fondazione Italiana per la Ricerca sul Cancro
Organisme : Deutsche Forschungsgemeinschaft
ID : EXC-2049 - 390688087
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG 11904
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG 15538
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : MultiUnit-5x1000 MCO 10.000
Organisme : The Italian Ministry of University and Scientific Research
ID : 20177E9EPY_002
Organisme : University of Milan
ID : PSR2020
Organisme : Italian Ministry of Health (Ricerca Corrente; 5×1000 funds RF-2016-02361540)
Informations de copyright
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
Références
Curr Opin Cell Biol. 2015 Oct;36:62-70
pubmed: 26201843
J Cell Biol. 2019 Mar 4;218(3):1066-1079
pubmed: 30591513
Nature. 2013 Jul 11;499(7457):233-7
pubmed: 23823722
Annu Rev Cell Dev Biol. 2010;26:315-33
pubmed: 19575647
Mol Med Rep. 2015 Jun;11(6):4303-8
pubmed: 25625869
Cell. 2005 Aug 12;122(3):473-83
pubmed: 16096065
PLoS Genet. 2018 Jan 30;14(1):e1007195
pubmed: 29381707
Cancer Res. 2005 Nov 1;65(21):9851-60
pubmed: 16267008
Adv Biol Regul. 2020 Jan;75:100693
pubmed: 32008962
Nat Rev Mol Cell Biol. 2014 Sep;15(9):577-90
pubmed: 25145849
Mol Cell Biol. 2003 Feb;23(3):933-49
pubmed: 12529399
J Cell Sci. 2005 Oct 1;118(Pt 19):4415-25
pubmed: 16159962
Nat Cell Biol. 2005 Jun;7(6):581-90
pubmed: 15895076
Pharmaceutics. 2021 Apr 14;13(4):
pubmed: 33920031
Nat Chem Biol. 2018 Aug;14(8):801-810
pubmed: 29915378
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Nat Med. 2012 Oct;18(10):1560-9
pubmed: 22983395
Nat Cell Biol. 2002 Apr;4(4):E97-100
pubmed: 11944043
Pharmacol Ther. 2015 Feb;146:132-49
pubmed: 25316657
Adv Sci (Weinh). 2022 Mar;9(9):e2103249
pubmed: 35098698
Mol Cell Biochem. 2011 Aug;354(1-2):301-9
pubmed: 21516337
J Am Soc Nephrol. 2016 Apr;27(4):1135-44
pubmed: 26271513
Nat Commun. 2021 May 5;12(1):2550
pubmed: 33953176
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Feb;1865(2):158575
pubmed: 31743753
Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6696-701
pubmed: 17420453
Adv Biol Regul. 2015 Jan;57:153-61
pubmed: 25294679
J Cell Sci. 2002 Oct 1;115(Pt 19):3807-15
pubmed: 12235291
Semin Cancer Biol. 2019 Dec;59:50-65
pubmed: 30922959
Nat Cell Biol. 2014 Jun;16(6):561-73
pubmed: 24859005
Hematol Oncol Stem Cell Ther. 2021 Dec;14(4):275-289
pubmed: 33744312
Trends Cell Biol. 2020 Sep;30(9):720-735
pubmed: 32674938
Mol Cell. 2018 Jul 19;71(2):343-351.e4
pubmed: 30029007
BMC Genomics. 2020 Jan 15;21(1):50
pubmed: 31941444
J Biol Chem. 2015 Mar 6;290(10):6086-105
pubmed: 25614622
Dev Cell. 2014 Mar 31;28(6):647-58
pubmed: 24697898
J Biol Chem. 2000 Nov 10;275(45):35600-6
pubmed: 10950958
Carcinogenesis. 2005 Mar;26(3):513-23
pubmed: 15358632
Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):E9125-E9134
pubmed: 30194235
Lancet. 1993 Oct 23;342(8878):1024-5
pubmed: 8105266
Cell. 2011 Jun 24;145(7):1012-22
pubmed: 21703446
Nat Cell Biol. 2020 Jan;22(1):26-37
pubmed: 31871317
Mol Biol Cell. 2005 Jan;16(1):84-96
pubmed: 15525681
Trends Cell Biol. 2019 Apr;29(4):339-359
pubmed: 30691999
Nature. 2006 Oct 12;443(7112):651-7
pubmed: 17035995
J Cell Biol. 2011 May 30;193(5):901-16
pubmed: 21624956
Curr Opin Cell Biol. 2008 Feb;20(1):85-90
pubmed: 18083360
Cancer Cell. 2006 Dec;10(6):515-27
pubmed: 17157791
Sci Adv. 2019 Jul 24;5(7):eaaw4197
pubmed: 31355333
Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):E8234-E8243
pubmed: 28835536
Mol Biol Cell. 2007 May;18(5):1850-60
pubmed: 17344481
Front Oncol. 2020 Mar 31;10:360
pubmed: 32296634
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Cancer Sci. 2017 May;108(5):941-951
pubmed: 28247964
Cancer Res. 1992 Mar 15;52(6):1399-405
pubmed: 1540948
Cancer Res. 2012 Aug 15;72(16):4130-40
pubmed: 22700880
Mol Biol Cell. 2011 Apr;22(7):964-75
pubmed: 21289086
Cancer Res. 2005 Jan 15;65(2):507-15
pubmed: 15695393
Front Biosci (Landmark Ed). 2014 Jan 01;19(4):687-706
pubmed: 24389213
EMBO J. 2010 Apr 7;29(7):1205-14
pubmed: 20186121
Biochem Soc Trans. 2006 Nov;34(Pt 5):846-50
pubmed: 17052212
Blood. 2012 Feb 16;119(7):1693-701
pubmed: 22174156
PLoS Genet. 2019 Apr 29;15(4):e1008088
pubmed: 31034465
Cancer Cell. 2017 Oct 9;32(4):444-459.e7
pubmed: 29017056
Biol Chem. 2015 Aug;396(8):831-48
pubmed: 25781681
J Cell Sci. 2003 Sep 15;116(Pt 18):3729-38
pubmed: 12890755
Curr Biol. 2013 Nov 4;23(21):2079-89
pubmed: 24206842