The application of an extracellular vesicle-based biosensor in early diagnosis and prediction of chemoresponsiveness in ovarian cancer

Abstract

ABSTRACTOvarian cancer (OVCA) is the most fatal gynecological cancer with late diagnosis and chemoresistance being the main obstacles of treatment success. Since there is no reliable approach to diagnosing patients at an early stage as well as predicting chemoresponsiveness, there is the urgent need to develop a diagnostic platform for such purposes. Extracellular vesicles (EVs) present as an attractive biomarker given their potential specificity and sensitivity to tumor sites. We have developed a novel sensor which utilizes cysteine functionalized gold nanoparticles to simultaneously bind to cisplatin (CDDP) and EVs affording us the advantage of predicting OVCA chemoresponsiveness, histologic subtypes, and early diagnosis using surface enhanced Raman spectroscopy. EVs were isolated and characterized from chemosensitive and resistant OVCA cells lines as well as pre-operative patient blood samples. The mechanistic role of plasma gelsolin (pGSN) in EV-mediated CDDP secretion in OVCA chemoresistance was investigated using standard cellular and molecular techniques. We determined that chemoresistant cells secrete significantly higher levels of small EVs (sEVs) and EVs containing CDDP (sEV-CDDP) compared with their sensitive counterparts. pGSN interacted with cortactin (CTTN) and both markers were significantly upregulated in chemoresistant patients’ tumors compared with the sensitive patients. Silencing pGSN decreased EV and EV-CDDP secretions in the resistant cells whereas its over-expression in sensitive cells upregulated EV and EV-CDDP secretion, suggesting the potential role of pGSN in EV-mediated CDDP export. sEV/CA125 ratio outperformed CA125 and sEV individually in predicting early stage, chemoresistance, residual disease, tumor recurrence, and patient survival. These findings highlight pGSN as a potential therapeutic target as well as providing a potential diagnostic platform to detect OVCA earlier and predict chemoresistance; an intervention that will positively impact patients’ survival.