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

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

Science (New York, N.Y.) (2017-09-16)

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 Brandis, Garold 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

PMID28912244

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.

MATERIALS

Product Number

Brand

Product Description

MBD0032

Sigma-Aldrich

Eubacteria FISH probe - ATTO488, Probe for fluorescence in situ hybridization (FISH), 20 µM in water

MBD0035

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Bacterial negative control FISH probe - Cy3, Probe for fluorescence in situ hybridization (FISH),20 μM in water

MBD0029

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Porphyromonas gingivalis FISH probe - Cy3, Probe for fluorescence in situ hybridization (FISH),20 μM in water

MBD0040

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Proteus FISH probe - Cy3, Probe for fluorescence in situ hybridization (FISH),20 μM in water

MBD0047

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Enterococcus faecium FISH probe – ATTO 488, Probe for fluorescence in situ hybridization (FISH), 20µM in water

MBD0050

Sigma-Aldrich

Akkermansia muciniphila FISH probe-ATTO488, Probe for fluorescence in situ hybridization (FISH), 20µM in water

MBD0048

Sigma-Aldrich

Enterococcus faecium FISH probe - Cy3, Probe for fluorescence in situ hybridization (FISH), 20µM in water

MBD0049

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Escherichia coli FISH probe -ATTO488, Probe for fluorescence in situ hybridization (FISH), 20µM in water

MBD0059

Sigma-Aldrich

Alphaproteobacteria FISH probe-Cy3, Probe for fluorescence in situ hybridization (FISH), 20 μM in water

MBD0033

Sigma-Aldrich

Eubacteria FISH probe - Cy3, Probe for fluorescence in situ hybridization (FISH)

MBD0028

Sigma-Aldrich

Porphyromonas gingivalis FISH probe - ATTO488, Probe for fluorescence in situ hybridization (FISH)

MBD0039

Sigma-Aldrich

Proteus FISH probe - ATTO488, Probe for fluorescence in situ hybridization (FISH),20 μM in water

MBD0041

Sigma-Aldrich

Akkermansia muciniphila FISH probe - Cy3, Probe for fluorescence in situ hybridization (FISH),20 μM in water

MBD0042

Sigma-Aldrich

Escherichia coli FISH probe - Cy3, Probe for fluorescence in situ hybridization (FISH)

MBD0034

Sigma-Aldrich

Bacterial negative control FISH probe - ATTO488, Probe for fluorescence in situ hybridization (FISH),20 μM in water