Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine
Open accessAbstract
In model systems, bacteria present in human pancreatic tumors confer resistance to the anticancer drug gemcitabine.
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Polychemotherapy and endocrine therapy can modulate alpha and beta diversity of microbiota, proposed to affect treatment-related adverse events and drug metabolism or efficacy.
“polychemotherapy and endocrine therapy (such as androgen deprivation) can modulate the alpha and beta diversities of the microbiota, which have been proposed to affect treatment-related adverse events27,28 as well as drug metabolism and efficacy29,30.”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [30]
The dominance of Proteobacteria in pancreatic cancer may reflect retrograde bacterial migration from the duodenum.
“This may reflect a retrograde bacterial migration from the duodenum, to which the pancreatic duct opens, as we have previously reported (16).”
From The human tumor microbiome is composed of tumor type–specific intracellular bacteria (2020) · cites this paper as [16]
Proteobacteria dominated the microbiome of pancreatic cancer, similarly to the normal duodenal microbiome.
“In contrast, Proteobacteria dominated the microbiome of pancreatic cancer, similarly to the normal duodenal microbiome makeup (16, 17, 48, 49).”
From The human tumor microbiome is composed of tumor type–specific intracellular bacteria (2020) · cites this paper as [16]
Bacterial and fungal pathogens can infiltrate PDAC.
“bacterial and fungal pathogens can infiltrate into PDAC264–266.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [266]
Gammaproteobacteria are present in human PDAC and can metabolize gemcitabine to its inactive form, potentially causing gemcitabine resistance.
“Geller et al. reported the presence of Gammaproteobacteria (GP), besides other bacteria, in human PDAC. Importantly, they reported that GP is able to metabolize gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form (2′,2′-difluorodeoxyuridine), suggesting that the presence of this bacteria in PDAC may be responsible for the tumor resistance to gemcitabine”
From Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes (2019) · cites this paper as Geller et al., 2017
Immunohistochemistry for bacterial lipopolysaccharide confirmed the presence of intratumoral bacteria in all PDAC samples evaluated.
“this approach confirmed the presence of intratumoral bacterial in all PDAC samples evaluated”
From Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes (2019) · cites this paper as Geller et al., 2017
Evidence suggests that intratumoral bacteria exist and are functionally active, with overlapping immunohistochemistry, immunofluorescence, electron microscopy, and sequencing data across about 10 cancer types.
“Emerging evidence also suggests the existence and functional activity of intratumoral bacteria, with overlapping immunohistochemistry, immunofluorescence, electron microscopy, and sequencing data on them in ~10 cancer types.”
From The microbiome and human cancer (2021) · cites this paper as [14]
Intratumor microbes have cancer-specific effects on chemoresistance via direct microbial metabolism (cytidine deaminase degradation of gemcitabine) in pancreatic cancer or indirect amplification of cancer cell autophagy in colorectal cancer.
“(iii) chemoresistance via direct microbial metabolism (cytidine deaminase degradation of gemcitabine) in pancreatic cancer or indirect amplification of cancer cell autophagy in colorectal cancer (14, 104)”
From The microbiome and human cancer (2021) · cites this paper as [14]
Presence of Gammaproteobacteria in murine colon cancer and human PDAC contributes to resistance against gemcitabine therapy.
“the presence of Gammaproteobacteria in murine colon cancer and human PDAC contributes to resistance against therapy with gemcitabine.198”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [198]
Intratumor Gammaproteobacteria can metabolize gemcitabine into its inactive form, leading to chemoresistance in a murine model of colon cancer.
“Geller et al. showed that intratumor Gammaproteobacteria in a tumor could metabolize gemcitabine into its inactive form leading to chemoresistance in a murine model of colon cancer [415].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [415]
Microbes regulate chemoresistance via direct drug metabolism.
“regulate chemoresistance via direct drug metabolism by microbes [415, 416]”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [415]
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References 30 · Cited by 1,817
- Authors
- Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D., Gavert, N., Zwang, Y., Cooper, Z. A., Shee, K., Thaiss, C. A., Reuben, A., Livny, J., Avraham, R., Frederick, D. T., Ligorio, M., Chatman, K., Johnston, S. E., Mosher, C. M., Brandis, A., Fuks, G., Gurbatri, C., Gopalakrishnan, V., Kim, M., Hurd, M. W., Katz, M., Fleming, J., Maitra, A., Smith, D. A., Skalak, M., Bu, J., Michaud, M., Trauger, S. A., Barshack, I., Golan, T., Sandbank, J., Flaherty, K. T., Mandinova, A., Garrett, W. S., Thayer, S. P., Ferrone, C. R., Huttenhower, C., Bhatia, S. N., Gevers, D., Wargo, J. A., Golub, T. R., & Straussman, R.
- Affiliations
- Weizmann Institute of Science (IL)
- Broad Institute (US)
- Massachusetts Institute of Technology (US)
- Brigham and Women's Hospital (US)
- Open University of Israel (IL)
- The University of Texas MD Anderson Cancer Center (US)
- Massachusetts General Hospital (US)
- Harvard University (US)
- Columbia University (US)
- Tel Aviv University (IL)
- University of Nebraska Medical Center (US)
- Corresponding author
- Geller, Leore T.
- Barzily-Rokni, Michal
- Straussman, Ravid
- ORCID
- 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.
- Brandis, Alexander
- Fuks, Garold
- Gurbatri, Candice
- Gopalakrishnan, Vancheswaran
- Kim, Michael
- Hurd, Mark W.
- Katz, Matthew
- Fleming, Jason
- Maitra, Anirban
- Smith, David A.
- Bu, Jeffrey
- 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
- Venue
- Science
- Published
- 2017-09-15
- Volume
- 357
- Issue
- 6356
- Pages
- 1156-1160
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5727343
- OpenAlex
- W2756403351
- Cited by
- 1,817
- References
- 30
- Citations by year
- 2026: 232 · 2025: 273 · 2024: 263 · 2023: 251 · 2022: 244 · 2021: 212 · 2020: 151 · 2019: 110 · 2018: 72 · 2017: 7
- FWCI
- 41.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Cancer Institute (award193897, U54CA112962)
- Israel Science Foundation (award193898, 1877/14)
- Moross Integrated Cancer Center (award309550)
- Fabrikant-Morse Families Research Fund for Humanity (award309551)
- Hymen T. Milgrom Trust (award309552)
- Rising Tide Foundation (award309553)
- Dr. Dvora and Haim Teitelbaum Endowment Fund (award309554)
- Tobias and Toni Gottesfeld Scholarship (award309555)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- gemcitabine resistance, chemoresistance, pancreatic ductal adenocarcinoma, Gammaproteobacteria, ciprofloxacin, gut microbiota, tumor microbiome
- MeSH terms
- Gemcitabine, Animals, Antimetabolites, Antineoplastic, Colonic Neoplasms, Deoxycytidine, Humans, Male, Mice, Inbred BALB C, Neoplasms, Experimental, Pancreatic Neoplasms, Drug Resistance, Neoplasm, Gammaproteobacteria, Carcinoma, Pancreatic Ductal, Mycoplasma hyorhinis, Mice
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