Porphyromonas gingivalis and Pancreatic Carcinogenesis in Mouse Models

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Project Summary In the US, pancreatic cancer is the fourth leading cause of cancer-related death and is responsible for over 40,500 annual deaths. Prognosis is poor because most pancreatic cancers are diagnosed late in the progression of the disease, with only 6% of patients alive 5 years after initial diagnosis. Understanding the etiology of pancreatic cancer is critical to implement steps towards prevention and may provide insights on how to detect this highly fatal disease. Several epidemiological studies to date support an association between periodontal disease and pancreatic cancer risk. A recent epidemiological study of a large European cohort, documented a prospective two-fold increase in risk of pancreatic cancer among individuals with elevated antibodies to the periodontal pathogen, Porphyromonas gingivalis. The presence of P. gingivalis in the human oral microbiome was also recently associated with a higher risk of pancreatic cancer, suggesting an etiological role for P. gingivalis in pancreatic cancer. We have established that P. gingivalis promotes low-grade chronic inflammation through distinct immunomodulatory mechanisms. We hypothesize that P. gingivalis oral infection in Kras mutant mice will accelerate pancreatic cancer as a result of the unique ability of this pathogen to function in immune modulation. In this proposal, we will establish a model of P. gingivalis-accelerated pancreatic cancer in Kras mutant mice (Aim 1). We will also use the Kras mutant mouse model to examine the ability of P. gingivalis to accelerate pancreatic cancer development induced by prior or subsequent caerulein- induced pancreatitis (Aim 2). This R03 is led by Dr. Caroline Genco at Tufts University. Dr. Genco is a leader in the field of P. gingivalis and chronic inflammation. Her laboratory has defined the role of innate immune pathways that contribute to P. gingivalis-induced inflammation and the role of immunomodulation in pathogen-induced low-grade chronic inflammation. Dr. Murtaugh at University of Utah (Human Genetics) will provide expertise in pancreatic cancer mouse models. Leveraging our combined experience, we are uniquely poised to carry out the aims designed to establish a model of P. gingivalis-induced pancreatic cancer. The proposed studies will provide proof of concept results and preliminary mechanistic insight into PanIIN initiation and progression and are highly likely to lead to in-depth mechanistic studies into the cause, treatment, and prevention of pancreatic cancer. Knowledge gained from the current proposal will guide the design of new targets for detection, treatment, and prevention in humans of this extraordinarily lethal cancer.