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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
JournalScience
Volume357
Issue6356
Pages1156-1160
Date Published2017 Sep 15
ISSN1095-9203
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.

DOI10.1126/science.aah5043
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28912244?dopt=Abstract

Alternate JournalScience
PubMed ID28912244
Grant ListP30 DK043351 / DK / NIDDK NIH HHS / United States