{Reference Type}: Journal Article
{Title}: Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer.
{Author}: Gambelli A;Nespolo A;Rampioni Vinciguerra GL;Pivetta E;Pellarin I;Nicoloso MS;Scapin C;Stefenatti L;Segatto I;Favero A;D'Andrea S;Mucignat MT;Bartoletti M;Lucia E;Schiappacassi M;Spessotto P;Canzonieri V;Giorda G;Puglisi F;Vecchione A;Belletti B;Sonego M;Baldassarre G;
{Journal}: EMBO Mol Med
{Volume}: 16
{Issue}: 5
{Year}: 2024 May 24
{Factor}: 14.26
{DOI}: 10.1038/s44321-024-00069-3
{Abstract}: 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.