Evaluating extracellular vesicles to monitor therapeutic intervention in ovarian cancer
Ovarian cancer (OvCa) has the highest mortality of all gynecological cancer, with a 5-year survival rate of 49%. Clear Cell Ovarian Carcinoma (CCOC), a rare subtype of OvCa, is often diagnosed in younger women and is characterized by dismal survival outcomes for late stage patients. This is because CCOC is inherently more resistant to chemotherapy compared to other subtypes. Extracellular Vesicles (EVs), which are small particles containing biomolecules secreted by all cells, including tumor cells, have been posited to prime the tumor microenvironment and promote tumor proliferation. Our study aimed to investigate whether proteins contained in tumor cell derived EV cargo reflect dose-dependent changes following chemotherapy and if they harbor proteins that can aid in monitoring therapeutic efficacy. We treated TOV21G cells, a CCOC cell line, with the chemotherapy agent cisplatin at different concentrations and profiled the proteome of treated cells and their secreted EVs. We observed significant, dose-dependent changes in the cellular proteome following treatment with cisplatin. Specifically, EphA2 and NEK10 were increased with increasing cisplatin concentration. These kinases have previously been reported to be involved in tumor proliferation, chemoresistance, and metastasis. EV proteomics analysis identified 5 proteins that were consistently significantly different in all treatment groups when compared to the untreated control. Functional analyses of proteins identified in the EV cargo of cisplatin-treated tumor cells showed an enrichment of biological processes related to cell cycle and DNA damage response. Overall, our study identified several targets that can help us explore mechanisms relating to CCOC progression and relapse. Developing a better understanding of how tumors utilize EVs to achieve drug resistance and proliferation can improve clinical outcomes for patients with chemo-resistant CCOC.