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

Abstract

AO_SCPLOWBSTRACTC_SCPLOWBreast, ovarian, digestive and lung adenocarcinomas are often associated with the accumulation of malignant cells in serous cavities. As PI3K is one of the most mutated pathways in cancer, we investigated the importance of oncogenic PI3K in this process. We analyzed tumor cell organization in ascites from carcinomas at diagnosis. In some malignant ascites, tumor cells grew as adhesive coherent masses. Ex-vivo patient-derived cell cultures with the addition of mesenchymal stem cells, as a model of tumoral stroma, favored the compaction of tumorospheres. Ascites-derived ovarian cancer cell lines frequently harbored PIK3CA mutations coexisting with other mutations. PI3K promoted the formation and maintenance of multicellular adhesive PIK3CA-mutant spheroids, promoting cell survival. Cultures in 3D conditions as opposed to cultures in cell monolayers increased chemotherapy resistance, which was overcome by PI3K inhibition. We identified a signaling pathway of interest for the treatment of cancer cells disseminated in serous cavities, limiting cancer progression. Graphical abstractSchematic representation of PI3K involvement in tumor cell aggregates from ascites. 1) Known involvement of PI3K in primary ovarian tumors. 2) PI3K participates in tumorosphere formation within the peritoneum (treatment with PI3K inhibitors causes a delay in the formation of clusters). 3) PI3K participates in the maintenance of tumorospheres and in resistance to conventional treatment for peritoneal carcinomatosis. PI3K is a target to prevent transcoelomic dissemination and maintenance of tumorospheres in patients with ovarian cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/777649v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@15d4fa2org.highwire.dtl.DTLVardef@1175601org.highwire.dtl.DTLVardef@10f801dorg.highwire.dtl.DTLVardef@a41771_HPS_FORMAT_FIGEXP M_FIG C_FIG