Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer

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 alpha 6 (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.In EOC ITGA6 is overexpressed and secreted by PT-res cells favoring the formation of a pro-metastatic niche, adhesion and invasion of the mesothelium. ITGA6 inhibition prevents the activation of pro-invasive pathways, leading to decreased metastasis formation and increased response to PT.PT treatment induces ITGA6 transcription and secretion, both in vitro and in vivo. ITGA6 confers resistance to PT and higher adhesion and metastatic ability to EOC cells by upregulating Snail protein via IGFR1-Src activation. Secreted ITGA6 favors EOC metastatic dissemination by modulating IGF1R signaling and Snail expression. ITGA6 targeting in vivo is feasible, prevents dissemination and improves PT response.In EOC ITGA6 is overexpressed and secreted by PT-res cells favoring the formation of a pro-metastatic niche, adhesion and invasion of the mesothelium. ITGA6 inhibition prevents the activation of pro-invasive pathways, leading to decreased metastasis formation and increased response to PT.