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Science DOI:10.1126/science.aah5043

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

Publication TypeJournal Article
Year of Publication2017
AuthorsGeller, LT, Barzily-Rokni, M, Danino, T, Jonas, OH, Shental, N, Nejman, D, Gavert, N, Zwang, Y, Cooper, ZA, Shee, K, Thaiss, CA, Reuben, A, Livny, J, Avraham, R, Frederick, DT, Ligorio, M, Chatman, K, Johnston, SE, Mosher, CM, Brandis, A, Fuks, G, Gurbatri, C, Gopalakrishnan, V, Kim, M, Hurd, MW, Katz, M, Fleming, J, Maitra, A, Smith, DA, Skalak, M, Bu, J, Michaud, M, Trauger, SA, Barshack, I, Golan, T, Sandbank, J, Flaherty, KT, Mandinova, A, Garrett, WS, Thayer, SP, Ferrone, CR, Huttenhower, C, Bhatia, SN, Gevers, D, Wargo, JA, Golub, TR, Straussman, R
Date Published2017 09 15
KeywordsAnimals, Antimetabolites, Antineoplastic, Carcinoma, Pancreatic Ductal, Colonic Neoplasms, Deoxycytidine, Drug Resistance, Neoplasm, Gammaproteobacteria, Humans, Male, Mice, Mice, Inbred BALB C, Mycoplasma hyorhinis, Neoplasms, Experimental, Pancreatic Neoplasms

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), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDD 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.


Alternate JournalScience
PubMed ID28912244
PubMed Central IDPMC5727343
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01 CA154426 / CA / NCI NIH HHS / United States
R01 CA169086 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
K08 CA160692 / CA / NCI NIH HHS / United States