Early Detection Research Network

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

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

Avraham R, Barshack I, Barzily-Rokni M, Bhatia SN, Brandis A, Bu J, Chatman K, Cooper ZA, Danino T, Ferrone CR, Flaherty KT, Fleming J, Frederick DT, Fuks G, Garrett WS, Gavert N, Geller LT, Gevers D, Golan T, Golub TR, Gopalakrishnan V, Gurbatri C, Hurd MW, Huttenhower C, Johnston SE, Jonas OH, Katz M, Kim M, Ligorio M, Livny J, Maitra A, Mandinova A, Michaud M, Mosher CM, Nejman D, Reuben A, Sandbank J, Shee K, Shental N, Skalak M, Smith DA, Straussman R, Thaiss CA, Thayer SP, Trauger SA, Wargo JA, Zwang Y

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Science, 2017, 357 (6356)

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