The lipid kinase PI3Kα is required for the cohesion and survival of cancer cells disseminated in serous cavities

Abstract

Running Title 38 -max 40PI3Kα controls tumour cell aggregation SUMMARY (174 WORDS) -MAX 175 WORDSPeritoneal carcinomatosis in ovarian cancer is often associated with ascites. In malignant ascites, tumour isolated cells and cell aggregates were present with a variability in size and numbers.Addition of mesenchymal stem cells, as a model of tumoural stroma, favoured aggregation of tumour cells. Because of the emerging concept that tri-dimensional cell culture could lead to increased resistance to conventional therapies, we investigated the importance of PI3Kα-driven protumourigenic and pro-chemoresistance signal in the formation of 3D model of ovarian cancer ascites. We demonstrated, through the use of selective pharmacological inhibitors of the PI3Kα isoform, the key role of this enzyme in the formation and maintenance of multicellular aggregates from ovarian origin. 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. We hence identified a signaling pathway of interest for the 2 treatment of advanced ovarian cancer, which could limit the progression of this poor prognosis cancer by ascites cancer cell dissemination.