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

By L. Geller, Michal Barzily-Rokni, Tal Danino, O. Jonas, Noam Shental, D. Nejman, N. Gavert, Yaara Zwang, Z. Cooper, K. Shee and 37 more. Science, 2017

1,535 citations recorded by the source corpus.

In model systems, bacteria present in human pancreatic tumors confer resistance to the anticancer drug gemcitabine. Debugging a cancer therapy Microbes contribute not only to the development of human diseases but also to the response of diseases to treatment. Geller et al. show that certain bacteria express enzymes capable of metabolizing the cancer chemotherapeutic drug gemcitabine into an inactive form. When bacteria were introduced into tumors growing in mice, the tumors became resistant to gemcitabine, an effect that was reversed by antibiotic treatment. Interestingly, a high percentage of human pancreatic ductal adenocarcinomas, a tumor type commonly treated with gemcitabine, contain the culprit bacteria. These correlative results raise the tantalizing possibility that the efficacy of an existing therapy for this lethal cancer might be improved by cotreatment with antibiotics. Science, this issue p. 1156 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.

Subfields: Biotechnology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/0ddd4015660b5bb8e3ff1bc7af34f47e2300f115

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In Biotechnology

1. B. Goodman
2. D. Saxena
3. H. Gardner

In Molecular Biology

1. J. Petrosino
2. Eran Elinav
3. James Robert White
4. Rob Knight
5. B. Goodman
6. A. Maitra
7. D. Saxena
8. Paul Scheet

In Oncology

1. B. Goodman
2. G. Miller
3. H. Gardner
4. L. Zitvogel
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Citations in the corpus

• Interaction between microbiota and immunity in health and disease (2020, background): “In addition, the presence of Gammaproteobacteria in murine colon cancer and human PDAC contributes to resistance against therapy with gemcitabine.(198) Interestingly, the intra-tumor microbiome in long-term survivors of PDAC patients exhibits higher microbial diversity, which may induce potent immun”
• The microbiome and cancer (2018, background): “It was recently shown that pancreatic cancer in humans contains a tumour microbiome enriched in members of the Gammaproteobacteria, including Mycoplasma hyorhinis [83].”
• Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes (2019, methodology): “Additionally, in the same set of FFPE samples, we detected the presence of bacterial lipopolysaccharide (LPS) by immunohistochemistry using an antibacterial lipopolysaccharide antibody, as previously performed (Figure S3B) (Geller et al., 2017).”
• Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments (2023, background): “hyorhinis in mice can develop resistance of pancreatic ductal adenocarcinoma (PDAC) to gemcitabine, and further investigation unveiled microbiome prevalence (especially γ-proteobacteria) in approximately 75% of human PDAC clinical samples [81].”
• The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression (2018, positive): “Targeting the microbiome has also been recently shown to synergize with cytotoxic chemotherapy in select cancers by affecting the metabolism of the chemotherapeutic agents (23).”
• The microbiome and human cancer (2021, background): “fragilis–derived toxin (22, 37, 38, 40, 41); (ii) CagA-mediated or IL-17– producing gd T cell–mediated inflammation in stomach and lung cancers, respectively (18, 103); (iii) chemoresistance through direct microbial metabolism (cytidine deaminase degradation of gemcitabine) in pancreatic cancer or i”