Spliceosomal components‐mediated intercellular communication: role in chemoresistance acquisition of ovarian cancer cells

Abstract

The relapse rate of ovarian cancer patients is about 85% with progression-free survival time less than two years. Cisplatin resistance of ovarian cancer cells cannot be explained only by mutations in DNA repair genes and increased expression of multidrug resistance proteins [Heijink et al., 2019]. It has been recently shown that cancer cells subjected to chemotherapy can secrete signaling molecules into the extracellular medium that contribute to the survival of neighboring tumor cells [Obenauf et al., 2015, Pavlyukov et al., 2018]. Thus, it is extremely important to take into account the role of intercellular signaling that occurs during therapy. In this study, we performed a comprehensive analysis of changes in secretomes of ovarian cancer cells under chemotherapy condition and demonstrated a new molecular mechanism for the acquisition of a more aggressive tumor phenotype. In addition to in vitro secretomes, we analyzed paired ascitic fluids from the same ovarian cancer patients before and after neoadjuvant chemotherapy (n = 10). We have shown that ascitic fluids after chemotherapy, as well as in vitro therapy-induced secretomes, contain components that contribute significantly to the formation of mesenchymal phenotype of primary cancer cell cultures, which was accompanied by increased migration and resistance to chemotherapy of intact tumor cells. Comprehensive proteomic analysis of secretomes and ascites revealed that extracellular fluids after chemotherapy are enriched with spliceosomal components. In addition, using fluorescence labelling and modified SILAC technology, we demonstrated the possibility of spliceosomal protein transport by extracellular vesicles from dying tumor cells to recipient cells. We suggest that splicing factors circulating in the extracellular space can “prepare” intact cancer cells for subsequent drug treatment. Therefore, combination of platinum-based drugs with spliceosomal inhibitors could improve the survival of patients with ovarian cancer.