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 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

doi:10.1126/science.aah5043

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

Science. 2017 Sep 15;357(6356):1156-1160. doi: 10.1126/science.aah5043.

Authors

Leore T Geller¹, Michal Barzily-Rokni², Tal Danino³, Oliver H Jonas^{4

5}, Noam Shental⁶, Deborah Nejman¹, Nancy Gavert¹, Yaara Zwang¹, Zachary A Cooper^{7

8}, Kevin Shee², Christoph A Thaiss⁹, Alexandre Reuben⁸, Jonathan Livny², Roi Avraham¹⁰, Dennie T Frederick¹¹, Matteo Ligorio¹², Kelly Chatman¹³, Stephen E Johnston², Carrie M Mosher², Alexander Brandis¹⁴, Garold Fuks¹⁵, Candice Gurbatri¹⁶, Vancheswaran Gopalakrishnan⁸, Michael Kim⁸, Mark W Hurd¹⁷, Matthew Katz⁸, Jason Fleming⁸, Anirban Maitra¹⁸, David A Smith², Matt Skalak³, Jeffrey Bu³, Monia Michaud¹⁹, Sunia A Trauger¹³, Iris Barshack^{20

21}, Talia Golan^{21

22}, Judith Sandbank²¹, Keith T Flaherty¹², Anna Mandinova^{2

23}, Wendy S Garrett^{2

19

24}, Sarah P Thayer²⁵, Cristina R Ferrone²⁶, Curtis Huttenhower^{2

27}, Sangeeta N Bhatia^{2

28

29

30

31

32

33}, Dirk Gevers², Jennifer A Wargo^{7

8}, Todd R Golub^{34

35

36}, Ravid Straussman³⁷

Affiliations

¹ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
⁴ Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵ Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Department of Mathematics and Computer Science, Open University of Israel, Raanana, Israel.
⁷ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
¹⁰ Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
¹¹ Department of Surgical Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹² Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
¹³ Small Molecule Mass Spectrometry Facility, Faculty of Arts and Sciences Division of Science, Harvard University, Cambridge, MA 02138, USA.
¹⁴ Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
¹⁵ Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
¹⁶ Department of Biomedical Engineering, Columbia University, New York City, NY 10027, USA.
¹⁷ Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁸ Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁹ Harvard T. H. Chan School of Public Health, Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Boston, MA 02115, USA.
²⁰ Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
²¹ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
²² Department of Oncology, Sheba Medical Center, Ramat Gan, Israel.
²³ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
²⁴ Dana-Farber Cancer Institute, Boston, MA 02115, USA.
²⁵ Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-6345, USA.
²⁶ Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Boston, MA 02114, USA.
²⁷ Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
²⁸ Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA.
²⁹ Howard Hughes Medical Institute (HHMI), Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA.
³⁰ Division of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
³¹ Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA.
³² Ludwig Center for Molecular Oncology, MIT, Cambridge, MA 02139, USA.
³³ Marble Center for Cancer Nanomedicine, MIT, Cambridge, MA 02139, USA.
³⁴ HHMI, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
³⁶ Harvard Medical School, Boston, MA 02115, USA.
³⁷ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. ravidst@weizmann.ac.il.

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 (CDD_L), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDD_L 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimetabolites, Antineoplastic / therapeutic use*
Carcinoma, Pancreatic Ductal / drug therapy*
Carcinoma, Pancreatic Ductal / microbiology*
Colonic Neoplasms / microbiology
Deoxycytidine / analogs & derivatives*
Deoxycytidine / therapeutic use
Drug Resistance, Neoplasm*
Gammaproteobacteria / isolation & purification
Gemcitabine
Humans
Male
Mice
Mice, Inbred BALB C
Mycoplasma hyorhinis / isolation & purification
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / microbiology
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / microbiology*

Substances

Antimetabolites, Antineoplastic
Deoxycytidine
Gemcitabine

Abstract

Publication types

MeSH terms

Substances

Grants and funding