Intra-tumor bacteria contribute to the resistance of pancreatic ductal adenocarcinoma to gemcitabine. intra-tumor bacteria in Pancreatic cancer

Tumor cells and the tumor microenvironment both contribute to drug resistance, a major obstacle in cancer care. Studying pancreatic ductal adenocarcinoma (PDAC), we explored the potential role of intra-tumor bacteria in conferring resistance to chemotherapy. Of 113 human PDACs analyzed, 76% were positive for bacteria, most commonly from the class Gammaproteobacteria. These bacteria were capable of metabolizing the chemotherapeutic drug gemcitabine into its inactive deaminated form, 2′,2′-difluorodeoxyuridine (dFdU). Deamination was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL). Likewise, in a mouse model, gemcitabine resistance was induced by intra-tumor Gammaproteobacteria, and was dependent on bacterial CDDL expression. Bacteria-dependent gemcitabine resistance was abrogated by co-treatment with the antibiotic ciprofloxacin.