Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy

Abstract

Epithelial Ovarian Cancer (EOC) is the second most common gynecologic malignancy in the United States, but the leading cause of gynecologic cancer death. Despite many achieving remission with first-line therapy (cytoreductive surgery and platinum-taxane chemotherapy), up to 80% of patients will recur and require additional treatment. Antibiotic therapy is frequently used during cancer treatments for both prophylaxis and treatment of infections. We assessed whether antibiotics would impact growth of EOC and sensitivity to cisplatin in murine models. Murine ID8 or ID8-VEGF EOC that were injected intraperitoneally exhibited accelerated growth and augmented cisplatin resistance following treatment with antibiotics (ABX) in both C57 BL/6J and NSG mice, indicating this effect was independent of an intact immune system. While antibiotics are critical for the care of the patient, they profoundly impacted the microbiome. RNAseq analysis of ID8 tumors from the NSG ABX groups showed enrichment of multiple cell proliferation and stem cell pathways, and increased expression of common stem cell genes such as SOX2, WNT and PAX2. The cancer stem cell population was increased with antibiotic treatment and further augmented by cisplatin treatment. Collectively, these studies indicate an intact microbiome provides a tumor suppressive microenvironment and enhances sensitivity to cisplatin.