Gammaproteobacteria Metabolize Gemcitabine to Promote Chemoresistance

Resistance to chemotherapy remains a major clinical challenge in patients with cancer. Nonmalignant cells in the tumor microenvironment, including tumor-associated fibroblasts, have been shown to influence drug resistance, prompting Geller, Barzily-Rokni, and colleagues to investigate the effect of human dermal fibroblasts (HDF) on sensitivity to the chemotherapeutic agent gemcitabine in colorectal and pancreatic cancer cells. Conditioned medium from HDFs could confer drug resistance, suggesting that a secreted factor mediates resistance. Filtering out particles larger than 0.45 μm prevented resistance, indicating that a large particle, such as a microbe, may be responsible for promoting resistance. Consistent with these findings, antibiotic-treated HDFs could not induce gemcitabine resistance. The HDFs were infected with Mycoplasma hyorhinis, which mediated gemcitabine resistance. In vivo, M. hyorhinis-infected colon cancer cells exhibited resistance to gemcitabine in tumor xenografts. Mechanistically, M. hyorhinis infected cells metabolized gemcitabine (2′,2′-difluorodeoxycytidine) to its inactive form (2′,2′-diflurodeoxyuridine) to confer gemcitabine resistance. Analysis of 27 other bacterial species identified 13 species that promoted gemcitabine resistance in colorectal cancer cells, which depended on expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD_L) to metabolize gemcitabine. CDD_L was expressed primarily in Gammaproteobacteria. In a mouse model of colon cancer, intratumor Gammaproteobacteria induced gemcitabine resistance, which depended on bacterial expression of CDD_L and was reversed by treatment with the antibiotic ciprofloxacin. Gemcitabine is often used to treat patients with pancreatic ductal adenocarcinoma (PDAC), and analysis of 113 human PDAC tumors revealed that 86 (76%) were positive for intratumor bacteria, most commonly Gammaproteobacteria. Most of the bacteria cultured from human PDACs were able to promote gemcitabine resistance in cultured cells. Collectively, these findings indicate that intratumor bacteria may promote resistance to gemcitabine, suggesting the potential for cotreatment with antibiotics to suppress this mechanism of chemoresistance.

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;357:1156–60.

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