%0 Journal Article
%T Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer.
%A Gambelli A
%A Nespolo A
%A Rampioni Vinciguerra GL
%A Pivetta E
%A Pellarin I
%A Nicoloso MS
%A Scapin C
%A Stefenatti L
%A Segatto I
%A Favero A
%A D'Andrea S
%A Mucignat MT
%A Bartoletti M
%A Lucia E
%A Schiappacassi M
%A Spessotto P
%A Canzonieri V
%A Giorda G
%A Puglisi F
%A Vecchione A
%A Belletti B
%A Sonego M
%A Baldassarre G
%J EMBO Mol Med
%V 16
%N 5
%D 2024 May 24
%M 38658801
%F 14.26
%R 10.1038/s44321-024-00069-3
%X 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.