Background: Ovarian cancer (OVCA) is the most fatal gynecological cancer with late diagnosis and plasma gelsolin (pGSN)-mediated chemoresistance representing the main obstacles to treatment success. Since there is no reliable approach to diagnosing patients at an early stage as well as predicting chemoresponsiveness, there is an urgent need to develop a diagnostic platform for such purposes. Small extracellular vesicles (sEVs) are attractive biomarkers given their potential accuracy for targeting tumor sites. Methods: We have developed a novel biosensor which utilizes cysteine-functionalized gold nanoparticles that simultaneously bind to cisplatin (CDDP) and plasma/cell-derived EVs, affording us the advantage of predicting OVCA chemoresponsiveness, and early diagnosis using surface-enhanced Raman spectroscopy. Results: We found that pGSN regulates cortactin (CTTN) content resulting in the formation of nuclear- and cytoplasmic-dense granules facilitating the secretion of sEVs carrying CDDP; a strategy used by resistant cells to survive CDDP action. The clinical utility of the biosensor was tested and subsequently revealed that the sEV/CA125 ratio outperformed CA125 and sEV individually in predicting early stage, chemoresistance, residual disease, tumor recurrence, and patient survival. Conclusion: These findings highlight pGSN as a potential therapeutic target and provide a potential diagnostic platform to detect OVCA earlier and predict chemoresistance; an intervention that will positively impact patient-survival outcomes.

Background Resistance to chemotherapy continues to be a challenge when treating epithelial ovarian cancer (EOC), contributing to low patient survival rates. While CA125, the conventional EOC biomarker, has been useful in monitoring patients’ response to therapy, there are no biomarkers used to predict treatment response prior to chemotherapy. Previous work in vitro showed that plasma gelsolin (pGSN) is highly expressed in chemoresistant EOC cell lines, where it is secreted in small extracellular vesicles (sEVs). Whether sEVs from tumour cells are secreted into the circulation of EOC patients and could be used to predict patient chemoresponsiveness is yet to be determined. This study aims to identify if sEV-pGSN in the circulation could be a predictive biomarker for chemoresistance in EOC. Methods Sandwich ELISA was used to measure pGSN concentrations from plasma samples of 96 EOC patients (primarily high grade serous EOC). sEVs were isolated using ExoQuick ULTRA and characterized using western blot, nanoparticle tracking analysis, and electron microscopy after which pGSN was measured from the sEVs. Patients were stratified as platinum sensitive or resistant groups based on first progression free interval (PFI) of 6 or 12 months. Results Total circulating pGSN was significantly decreased and sEV-pGSN increased in patients with a PFI ≤ 12 months (chemoresistant) compared to those with a PFI > 12 months (chemosensitive). The ratio of total pGSN to sEV-pGSN further differentiated these groups and was a strong predictive marker for chemoresistance (sensitivity: 73.91%, specificity: 72.46%). Predetermined CA125 was not different between chemosensitive and chemoresistant groups and was not predictive of chemoresponsiveness prior to treatment. When CA125 was combined with the ratio of total pGSN/sEV-pGSN, it was a significant predictor of chemoresponsiveness, but the test performance was not as robust as the total pGSN/sEV-pGSN alone. Conclusions Total pGSN/sEV-pGSN was the best predictor of chemoresponsiveness prior to treatment, outperforming the individual biomarkers (CA125, total pGSN, and sEV-pGSN). This multianalyte predictor of chemoresponsiveness could help to inform physicians’ treatment and follow up plan at the time of EOC diagnosis, thus improving patients’ outcomes.

Ovarian 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.