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

Laura M. Chambers, Emily L. Esakov, Chad Braley, Lexie Trestan, Zahraa Alali, View ORCID ProfileDefne Bayik, Justin D. Lathia, Naseer Sangwan, Peter Bazeley, Amy S. Joehlin-Price, Mohammed Dwidar, Adeline Hajjar, Philip P. Ahern, Jan Claesen, Peter Rose, Roberto Vargas, Chad Michener, View ORCID ProfileOfer Reizes
doi: https://doi.org/10.1101/2020.06.16.155226
Laura M. Chambers
1Division of Gynecologic Oncology; Obstetrics, Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, OH
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Emily L. Esakov
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Chad Braley
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Lexie Trestan
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Zahraa Alali
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Defne Bayik
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • ORCID record for Defne Bayik
Justin D. Lathia
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
8Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH
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Naseer Sangwan
3Microbiome Analytics and Composition Core Facility, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH
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Peter Bazeley
4Department of Quantitative Health Services, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland OH
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Amy S. Joehlin-Price
6Department of Gynecologic Pathology, Pathology and Lab Medicine Institute, Cleveland Clinic Foundation, Cleveland OH
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Mohammed Dwidar
5Microbial Culture and Engineering Facility, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland OH
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Adeline Hajjar
7Gnotobiotic Core Facility, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH
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Philip P. Ahern
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Jan Claesen
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Peter Rose
1Division of Gynecologic Oncology; Obstetrics, Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, OH
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Roberto Vargas
1Division of Gynecologic Oncology; Obstetrics, Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, OH
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Chad Michener
1Division of Gynecologic Oncology; Obstetrics, Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, OH
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Ofer Reizes
2Department of Cardiovascular and Metabolic Sciences, Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
8Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH
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  • ORCID record for Ofer Reizes
  • For correspondence: reizeso@ccf.org
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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 either metronidazole, ampicillin, vancomycin, and neomycin (ABX) containing or control water 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 asses for microbial population effects over time.

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 ABX treated tumor cells was also increased.

Conclusion Collectively, these studies indicate an intact microbiome provides a tumor suppressive microenvironment and enhances sensitivity to cisplatin.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Co-First Authors

Copyright 
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Posted September 11, 2020.
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Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy
Laura M. Chambers, Emily L. Esakov, Chad Braley, Lexie Trestan, Zahraa Alali, Defne Bayik, Justin D. Lathia, Naseer Sangwan, Peter Bazeley, Amy S. Joehlin-Price, Mohammed Dwidar, Adeline Hajjar, Philip P. Ahern, Jan Claesen, Peter Rose, Roberto Vargas, Chad Michener, Ofer Reizes
bioRxiv 2020.06.16.155226; doi: https://doi.org/10.1101/2020.06.16.155226
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Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy
Laura M. Chambers, Emily L. Esakov, Chad Braley, Lexie Trestan, Zahraa Alali, Defne Bayik, Justin D. Lathia, Naseer Sangwan, Peter Bazeley, Amy S. Joehlin-Price, Mohammed Dwidar, Adeline Hajjar, Philip P. Ahern, Jan Claesen, Peter Rose, Roberto Vargas, Chad Michener, Ofer Reizes
bioRxiv 2020.06.16.155226; doi: https://doi.org/10.1101/2020.06.16.155226

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