Role of Gut Microbiome in Smoking Induced Promotion of Pancreatic Cancer

Birmingham Va Medical Center, Birmingham AL

Investigators

Abstract

Project Summary Pancreatic cancer (PDAC) is the 3rd most common cause of cancer-related mortality in the US. Our veterans and military personnel bear significant brunt of this disease. One of the major obstacles in devising effective treatment strategies against PDAC is the incomplete understanding of its pathogenesis. For instance, smoking is one of the major life style factors, which affects PDAC incidence and outcomes. However, our understanding of the mechanism(s) by which smoking affects PDAC development is still rudimentary. Thus, to develop novel and effective treatment strategies, we need a better understanding of the pathogenesis of PDAC. Our recent work has demonstrated that gut microbiome modulates adaptive immune response and promotes PDAC growth and metastases. Interestingly, few studies suggest that cigarette smoking significantly impact gut microbiome. Whether, this modulation of gut microbiome in any way mediates the pro-tumorigenic effects of smoking is not known. Intriguingly, our preliminary data in animal models suggest that gut microbiome is critical for the smoking induced tumor initiation and progression. Furthermore, with respect to the mechanism, our preliminary data suggest that smoking induced dysbiosis attenuates anti-cancer immune response. The current study is the next logical step and clinical investigation of the findings generated from the pre-clinical models. Based on our preliminary studies we have hypothesized that ‘the cigarette smoking alters gut microbiome, which in turn promotes tumor initiation and progression in a immune dependent fashion. This hypothesis will be tested through a combination of a clinical, observational, non-interventional study in humans, and translational studies in Human Gut Microbiome Avatar Mice (AVATAR) generated using the samples collected from humans. The study will be executed through the following three specific aims: In Aim 1, to characterize the effect of smoking on gut metagenome and metabolome, stool samples will be collected from smokers and non-smoker generally healthy volunteers as well as PDAC patients, and analyzed by shotgun meta-genomics (for gut metagenome) and LC-MS (unbiased-metabolome). This analysis will help elucidate the specific gut microbial colonies as well as metabolites, which are enriched in the gut of smokers and might contribute to the increased incidence and worse outcomes of PDAC and other cancers in them. In Aim 2, to directly evaluate the effect of the smoking induced dysbiosis on PDAC growth and to elucidate the mechanism of this effect, we will leverage AVATAR model. Stool from healthy volunteers (smokers and non-smokers, in aim 1), will be transplanted into germ free genetically engineered mouse models of PDAC to yield patient specific AVATAR mice. The tumor initiation and progression in AVATAR mice generated from the stool of smokers (healthy volunteers/PDAC patients) will be measured, and compared with those generated from stools of non- smokers. These studies will provide direct evidence whether gut microbiome of smokers promote tumor initiation and/or progression, when compared to that of non-smokers. Finally, in Aim 3, we will build on our preliminary studies which suggest that smoking induced pro-tumorigenic gut microbiome promotes cancer progression. Specifically, we will evaluate therapeutic strategies by which the pro-tumorigenic effect of gut microbiome from smokers can be negated. Impact Statement: Pancreatic cancer is a leading source of morbidity and mortality in the veterans population. Moreover, tobacco product use is alarmingly high in the military veterans, with 1 in 3 using some form of tobacco. Our study can potentially uncover a new molecular pathway of pancreatic cancer growth in smokers, which can be easily translated into the clinical paradigm for management of these patients