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Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.

ABSTRACT: Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

SUBMITTER: Geller LT

PROVIDER: S-EPMC5727343 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.

Geller Leore T LT Barzily-Rokni Michal M Danino Tal T Jonas Oliver H OH Shental Noam N Nejman Deborah D Gavert Nancy N Zwang Yaara Y Cooper Zachary A ZA Shee Kevin K Thaiss Christoph A CA Reuben Alexandre A Livny Jonathan J Avraham Roi R Frederick Dennie T DT Ligorio Matteo M Chatman Kelly K Johnston Stephen E SE Mosher Carrie M CM Brandis Alexander A Fuks Garold G Gurbatri Candice C Gopalakrishnan Vancheswaran V Kim Michael M Hurd Mark W MW Katz Matthew M Fleming Jason J Maitra Anirban A Smith David A DA Skalak Matt M Bu Jeffrey J Michaud Monia M Trauger Sunia A SA Barshack Iris I Golan Talia T Sandbank Judith J Flaherty Keith T KT Mandinova Anna A Garrett Wendy S WS Thayer Sarah P SP Ferrone Cristina R CR Huttenhower Curtis C Bhatia Sangeeta N SN Gevers Dirk D Wargo Jennifer A JA Golub Todd R TR Straussman Ravid R

Science (New York, N.Y.) 20170901 6356

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD<sub>L</sub>), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was i ...[more]

PMID: 28912244

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Project description:BackgroundUnderstanding drivers of antibiotic resistance evolution is fundamental for designing optimal treatment strategies and interventions to reduce the spread of antibiotic resistance. Various cytotoxic drugs used in cancer chemotherapy have antibacterial properties, but how bacterial populations are affected by these selective pressures is unknown. Here we test the hypothesis that the widely used cytotoxic drug methotrexate affects the evolution and selection of antibiotic resistance.MethodsFirst, we determined methotrexate susceptibility (IC90) and selective abilities in a collection of Escherichia coli and Klebsiella pneumoniae strains with and without pre-existing trimethoprim resistance determinants. We constructed fluorescently labelled pairs of E. coli MG1655 differing only in trimethoprim resistance determinants and determined the minimum selective concentrations of methotrexate using flow-cytometry. We further used an experimental evolution approach to investigate the effects of methotrexate on de novo trimethoprim resistance evolution.FindingsWe show that methotrexate can select for acquired trimethoprim resistance determinants located on the chromosome or a plasmid. Additionally, methotrexate co-selects for genetically linked resistance determinants when present together with trimethoprim resistance on a multi-drug resistance plasmid. These selective effects occur at concentrations 40- to >320-fold below the methotrexate minimal inhibitory concentration.InterpretationOur results strongly suggest a selective role of methotrexate for virtually any antibiotic resistance determinant when present together with trimethoprim resistance on a multi-drug resistance plasmid. The presented results may have significant implications for patient groups strongly depending on effective antibiotic treatment.FundingPJJ was supported by UiT The Arctic University of Norway and the Northern Norway Regional Health Authority (SFP1292-16/HNF1586-21) and JPI-EC-AMR (Project 271,176/H10). DIA was supported by the Swedish Research Council (grant 2017-01,527). The publication charges for this article have been funded by a grant from the publication fund of UiT The Arctic University of Norway.

Dataset Information

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.

Publications

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.

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