Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer.
Integrin
Metastasis
Ovarian Cancer
chemoresistance
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
24 Apr 2024
24 Apr 2024
Historique:
received:
03
07
2023
accepted:
04
04
2024
revised:
27
03
2024
medline:
25
4
2024
pubmed:
25
4
2024
entrez:
24
4
2024
Statut:
aheadofprint
Résumé
Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.
Identifiants
pubmed: 38658801
doi: 10.1038/s44321-024-00069-3
pii: 10.1038/s44321-024-00069-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministero della Salute (Italy Ministry of Health)
ID : CRO Aviano Ricerca Corrente core grant
Organisme : Ministero della Salute (Italy Ministry of Health)
ID : CO-2018-12367051
Organisme : Ministero della Salute (Italy Ministry of Health)
ID : GR-2016-02361041
Organisme : Ministero degli Affari Esteri e della Cooperazione Internazionale (MAECI)
ID : PGR01036
Organisme : Ministero dell'Università e della Ricerca (MUR)
ID : ARS01_00568
Organisme : Fondazione AIRC per la ricerca sul cancro ETS (AIRC)
ID : IG 26253
Organisme : Fondazione AIRC per la ricerca sul cancro ETS (AIRC)
ID : IG 20061
Organisme : Fondazione AIRC per la ricerca sul cancro ETS (AIRC)
ID : MFAG 24321
Organisme : CRO-Aviano 5X1000 grants
ID : Cancer Specific
Informations de copyright
© 2024. The Author(s).
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