SUMMARYObjectivePeritoneal carcinomatosis in ovarian cancer is often associated with ascites. Because of the emerging concept that multicellular cell growth conditions can lead to increased resistance to conventional therapies, we investigated the importance of PI3Kα-driven pro-tumorigenic and pro-chemoresistance signals in the formation of a 3D model of ovarian cancer ascites.MethodsWe retrospectively analysed tumour cell aggregation and ascites composition in ovarian cancer adenocarcinomas at diagnosis with patient survival clinical data, then set up an ex-vivo 3D model. PI3K inhibition covered the full pharmacological arsenal available to target PI3K activity (pan-PI3K or isoform-selective inhibitors). We quantified cell survival, metabolism and cohesion of multicellular aggregates after treatment with PI3K inhibitors and/or cisplatin.ResultsIn malignant ascites, isolated tumour cells and cell aggregates were present with variability in size and number and aggregate-poor ascites predicted a poorer survival of ovarian adenocarcinoma patients. Ex-vivo patient-derived cell culture with the addition of mesenchymal stem cells, as a model of tumoural stroma, favoured aggregation of tumour cells. We demonstrated, by use of selective inhibitors of the PI3Kα isoform, its key role in the formation and maintenance of multicellular aggregates. This role did not depend solely on a pro-survival activity of PI3Kα but could be linked to changes in cell/cell adhesion. Finally, PI3Kα-selective inhibitors were also equally efficient in the presence of cisplatin.ConclusionWe have identified a signalling pathway of interest for the treatment of advanced ovarian cancer, which could limit the progression of this cancer.
Oncolytic adenovirus inhibits malignant ascites of advanced ovarian cancer via reprograming ascitic immune microenvironment