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

Research output: Contribution to journalArticle

139 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1156-1160
Number of pages5
JournalScience
Volume357
Issue number6356
DOIs
StatePublished - Sep 15 2017

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gemcitabine
Gammaproteobacteria
Bacteria
Colonic Neoplasms
Pharmaceutical Preparations
Cytidine Deaminase
Neoplasms
Ciprofloxacin
Drug Resistance
Protein Isoforms
Adenocarcinoma
Anti-Bacterial Agents
Enzymes

ASJC Scopus subject areas

  • General

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Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D., ... Straussman, R. (2017). Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science, 357(6356), 1156-1160. https://doi.org/10.1126/science.aah5043

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

In: Science, Vol. 357, No. 6356, 15.09.2017, p. 1156-1160.

Research output: Contribution to journalArticle

Geller, 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 2017, 'Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine', Science, vol. 357, no. 6356, pp. 1156-1160. https://doi.org/10.1126/science.aah5043
Geller LT, Barzily-Rokni M, Danino T, Jonas OH, Shental N, Nejman D et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017 Sep 15;357(6356):1156-1160. https://doi.org/10.1126/science.aah5043
Geller, Leore T. ; Barzily-Rokni, Michal ; Danino, Tal ; Jonas, Oliver H. ; Shental, Noam ; Nejman, Deborah ; Gavert, Nancy ; Zwang, Yaara ; Cooper, Zachary A. ; Shee, Kevin ; Thaiss, Christoph A. ; Reuben, Alexandre ; Livny, Jonathan ; Avraham, Roi ; Frederick, Dennie T. ; Ligorio, Matteo ; Chatman, Kelly ; Johnston, Stephen E. ; Mosher, Carrie M. ; Brandis, Alexander ; Fuks, Garold ; Gurbatri, Candice ; Gopalakrishnan, Vancheswaran ; Kim, Michael ; Hurd, Mark W. ; Katz, Matthew ; Fleming, Jason ; Maitra, Anirban ; Smith, David A. ; Skalak, Matt ; Bu, Jeffrey ; Michaud, Monia ; Trauger, Sunia A. ; Barshack, Iris ; Golan, Talia ; Sandbank, Judith ; Flaherty, Keith T. ; Mandinova, Anna ; Garrett, Wendy S. ; Thayer, Sarah P ; Ferrone, Cristina R. ; Huttenhower, Curtis ; Bhatia, Sangeeta N. ; Gevers, Dirk ; Wargo, Jennifer A. ; Golub, Todd R. ; Straussman, Ravid. / Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. In: Science. 2017 ; Vol. 357, No. 6356. pp. 1156-1160.
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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.",
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AU - Geller, Leore T.

AU - Barzily-Rokni, Michal

AU - Danino, Tal

AU - Jonas, Oliver H.

AU - Shental, Noam

AU - Nejman, Deborah

AU - Gavert, Nancy

AU - Zwang, Yaara

AU - Cooper, Zachary A.

AU - Shee, Kevin

AU - Thaiss, Christoph A.

AU - Reuben, Alexandre

AU - Livny, Jonathan

AU - Avraham, Roi

AU - Frederick, Dennie T.

AU - Ligorio, Matteo

AU - Chatman, Kelly

AU - Johnston, Stephen E.

AU - Mosher, Carrie M.

AU - Brandis, Alexander

AU - Fuks, Garold

AU - Gurbatri, Candice

AU - Gopalakrishnan, Vancheswaran

AU - Kim, Michael

AU - Hurd, Mark W.

AU - Katz, Matthew

AU - Fleming, Jason

AU - Maitra, Anirban

AU - Smith, David A.

AU - Skalak, Matt

AU - Bu, Jeffrey

AU - Michaud, Monia

AU - Trauger, Sunia A.

AU - Barshack, Iris

AU - Golan, Talia

AU - Sandbank, Judith

AU - Flaherty, Keith T.

AU - Mandinova, Anna

AU - Garrett, Wendy S.

AU - Thayer, Sarah P

AU - Ferrone, Cristina R.

AU - Huttenhower, Curtis

AU - Bhatia, Sangeeta N.

AU - Gevers, Dirk

AU - Wargo, Jennifer A.

AU - Golub, Todd R.

AU - Straussman, Ravid

PY - 2017/9/15

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N2 - 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.

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