Oral bacteria accelerate pancreatic cancer development in mice

Abstract

ObjectiveEpidemiological studies highlight an association between pancreatic ductal adenocarcinoma (PDAC) and oral carriage of the anaerobic bacteriumPorphyromonas gingivalis, a species highly linked to periodontal disease. We analysed the potential forP. gingivalisto promote pancreatic cancer development in an animal model and probed underlying mechanisms.DesignWe trackedP. gingivalisbacterial translocation from the oral cavity to the pancreas following administration to mice. To dissect the role ofP. gingivalisin PDAC development, we administered bacteria to a genetically engineered mouse PDAC model consisting of inducible acinar cell expression of mutantKras(Kras+/LSL-G12D; Ptf1a-CreER, iKC mice). These mice were used to study the cooperative effects ofKrasmutation andP. gingivalison the progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. The direct effects ofP. gingivalison acinar cells and PDAC cell lines were studied in vitro.ResultsP. gingivalismigrated from the oral cavity to the pancreas in mice and can be detected in human PanIN lesions. RepetitiveP. gingivalisadministration to wild-type mice induced pancreatic acinar-to-ductal metaplasia (ADM), and altered the composition of the intrapancreatic microbiome. In iKC mice,P. gingivalisaccelerated PanIN to PDAC progression. In vitro,P. gingivalisinfection induced acinar cell ADM markers SOX9 and CK19, and intracellular bacteria protected PDAC cells from reactive oxygen species-mediated cell death resulting from nutrient stress.ConclusionTaken together, our findings demonstrate a causal role forP. gingivalisin pancreatic cancer development in mice.