Disruption of the Gut Microbiota Attenuates Epithelial Ovarian Cancer Sensitivity to Cisplatin Therapy

Abstract Background: 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, 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, although this profoundly impacts the gut microbiome. Multiple studies suggest that an unperturbed gut microbiome may provide a protective microenvironment, and disruption may be permissive to tumor growth and chemotherapy resistance, including platinum agents. Experimental Design: We assessed whether antibiotic therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given control or antibiotic (ABX) containing water (metronidazole, ampicillin, vancomycin, and neomycin) for two weeks before being intraperitoneally injected with murine ID8 or ID8-VEGF EOC cells. Tumors were monitored and cisplatin therapy was administered weekly until endpoint. Stool was collected throughout the study to assess for microbial population effects over time. Cecal microbiota transplants (CMTs) of contents derived from ABX or control treated donor mice were performed on ABX treated recipient mice. Results: Both immune competent and immune compromised ID8 and ID8 VEGF tumor-bearing mice demonstrated a decreased response to cisplatin therapy in ABX treated groups with an increase in overall tumor burden. RNAseq analysis showed enrichment of multiple cell proliferation and stem cell pathways, and stem cell genes SOX2, WNT and PAX2. The self-renewal of cancer cells derived from tumors of ABX treated mice was increased compared to tumors from control mice, indicative of a microbiota derived tumor suppressor. Conclusion: Collectively, these studies indicate an intact microbiome provides a tumor suppressor and maintains chemosensitivity that is disrupted by ABX treatment.