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

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

نتاج البحث: نشر في مجلةمقالةمراجعة النظراء


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.

اللغة الأصليةالإنجليزيّة
الصفحات (من إلى)1156-1160
عدد الصفحات5
مستوى الصوت357
رقم الإصدار6356
المعرِّفات الرقمية للأشياء
حالة النشرنُشِر - 15 سبتمبر 2017

ملاحظة ببليوغرافية

Funding Information:
R.S. is funded by the Israel Science Foundation (grant no. 1877/14), the Moross Integrated Cancer Center, the Fabrikant-Morse Families Research Fund for Humanity, the Hymen T. Milgrom Trust, Rising Tide Foundation, the Dr. Dvora and Haim Teitelbaum Endowment Fund, the Tobias and Toni Gottesfeld Scholarship, and by A. Shashua, Israel. R.S. is the incumbent of the Roel C. Buck Career Development Chair. T.R.G. is funded by the Howard Hughes Medical Institute and by the U.S. National Cancer Institute (grant no. U54CA112962). C.H. is on the scientific advisory board of Evelo Biosciences. J.A.W. is a paid advisor for GlaxoSmithKline, Roche/ Genentech, Novartis, and Bristol-Myers Squibb.

Publisher Copyright:
© 2017, American Association for the Advancement of Science. All rights reserved.


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