3 years ago

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

Zachary A. Cooper, Talia Golan, Sarah P. Thayer, Alexandre Reuben, Deborah Nejman, Alexander Brandis, Matthew Katz, Matt Skalak, Jonathan Livny, Carrie M. Mosher, Dennie T. Frederick, Michal Barzily-Rokni, Vancheswaran Gopalakrishnan, Garold Fuks, Stephen E. Johnston, Roi Avraham, Todd R. Golub, Oliver H. Jonas, Nancy Gavert, Noam Shental, Iris Barshack, Jason Fleming, Christoph A. Thaiss, Ravid Straussman, Wendy S. Garrett, Mark W. Hurd, Jennifer A. Wargo, Michael Kim, Candice Gurbatri, Dirk Gevers, Curtis Huttenhower, Monia Michaud, Matteo Ligorio, Judith Sandbank, Tal Danino, Yaara Zwang, Keith T. Flaherty, David A. Smith, Anirban Maitra, Kevin Shee, Leore T. Geller, Kelly Chatman, Sangeeta N. Bhatia, Cristina R. Ferrone, Anna Mandinova, Sunia A. Trauger, Jeffrey Bu

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.

Publisher URL: http://science.sciencemag.org/cgi/content/short/357/6356/1156

DOI: 10.1126/science.aah5043

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