Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.
Leore T GellerMichal Barzily-RokniTal DaninoOliver H JonasNoam ShentalDeborah NejmanNancy S GavertYaara ZwangZachary A CooperKevin SheeChristoph A ThaissAlexandre ReubenJonathan LivnyRoi AvrahamDennie T FrederickMatteo LigorioKelly ChatmanStephen E JohnstonCarrie M MosherAlexander BrandisGarold FuksCandice R GurbatriVancheswaran GopalakrishnanMichael P KimMark W HurdMatthew KatzJason B FlemingAnirban MaitraDavid A SmithMatt SkalakJeffrey BuMonia MichaudSunia A TraugerIris BarshackTalia GolanJudith SandbankKeith T FlahertyAnna MandinovaWendy S GarrettSarah P ThayerCristina R FerroneCurtis HuttenhowerSangeeta N BhatiaDirk GeversJennifer A WargoTodd R GolubRavid StraussmanPublished in: Science (New York, N.Y.) (2018)
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.