ITGA6 is a key molecule in driving metastatization of platinum resistant epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is a relatively rare disease usually diagnosed in advanced stages (III and IV stage). Standard of care includes radical surgery followed by platinum-based chemotherapy. Yet, 15% to 30% of EOC patients have a primary platinum-resistant or refractory disease and more than 70% of originally platinum-sensitive advanced stages patients will develop a resistant disease disseminated in the abdomen and pelvis. For these reasons, the net five-year survival by stage is only of 26% and 13% for stage III and IV, respectively. The resistance to chemotherapy is one of the major challenges cancer research faces nowadays. In our lab, we have established several Platinum (PT) resistant (PT-res) cellular models to better understand the molecular pathways that could guide PT-resistance in ovarian cancer. We observed that one of the common features of these PT-res cells was the higher ability to adhere on the mesothelial cells respect to their sensitive counterpart, a fundamental capacity for driving cell dissemination into the peritoneal cavity. My PhD project focused the attention on the dissection of the molecular basis of the higher adhesion capability of PT-res cells to possibly identify new therapeutic targets to overcome EOC peritoneal dissemination. We found all tested PT-res cells over-expressed the integrin alpha 6 (ITGA6) protein that in turn mediated their higher ability to adhere and migrate on the specific substrate laminin (LM) and on mesothelial cells. Using pharmacological and genetic tools, we showed that ITGA6 expression was linked to a higher capacity of PT-res cells to form ovaryspheres in vitro and to grow and disseminate in vivo. Molecular analyses next demonstrated that under PT treatment positively regulated ITGA6 gene promoter activity by via the SP1 transcription factor, possibly explaining the higher ITGA6 expression in PT-res cells. Moreover, PT-treatment also induced an active secretion of ITGA6. Once secreted, ITGA6 on one side primed mesothelial cells to form a pro-metastatic niche and, on the other, favoured the spreading of neighbour tumour cells. Mechanistically, the engagement of ITGA6 with LM positively regulated Snail expression favouring cell adhesion and spreading. These in vitro data were recapitulated in the human pathology since we found higher ITGA6 levels in the ascitic fluids of EOC patients with a PT-resistant disease and also demonstrated that higher levels of circulating ITGA6 could be found in the plasma of EOC after PT-based chemotherapy. Altogether, our collected data suggested that ITGA6 could be a reasonable druggable target to prevent EOC metastatization and dissemination in the peritoneal cavity, for instance by the use of specific blocking antibodies. Moreover, since ITGA6 is easily quantifiable in the circulation of EOC patients it could be used as predictive biomarkers to identify patients that could not respond to the standard PT-based chemotherapy