Gastrointestinal microbiota interactions modulating gastric cancer progression

点击翻译按钮获取中文摘要

PROJECT SUMMARY Gastric cancer is the fourth-leading cause of death worldwide and 80% of cases are attributed Helicobacter pylori (Hp) infection. The precise mechanism for how Hp promotes gastric cancer remains unclear. Intestinal type gastric cancer, the most common histologic type, is thought to arise from a series of tissues changes triggered by chronic inflammation caused by Hp, starting with loss of acid-producing parietal cells (gastric atrophy) and the appearance of metaplastic cells that may lead to dysplasia and gastric cancer. Bacterial factors such as the secreted toxin CagA, as well as host behavioral factors like smoking and diet, contribute to gastric cancer risk. However, only 1-2% of people infected with Hp will ultimately develop gastric cancer and among gastric cancer cases more than half have lost Hp colonization by the time of cancer diagnosis. The tissue changes associated with metaplasia and dysplasia (less acid, altered mucin expression and glycosylation) can favor outgrowth of oral bacteria in the stomach. Thus, additional factors, including other microbes, may contribute to gastric cancer etiology. Fusobacterium nucleatum (Fn) is a member of the oral microbiota but has also been implicated in colorectal cancer through microbial sequencing of human tumors and experimental manipulation in both xenograft and genetically modified mouse models. More recently Fn has been found in advanced gastric lesions and gastric cancer, in an apparent mutually exclusive relationship with Hp. We found that 19% of patients in a Pacific Northwest (PNW) gastric cancer cohort had gastric infection by (Fn). In mice, our preliminary data show Fn is a poor colonizer of the healthy stomach but robustly colonized the stomach during the context of KRAS-driven metaplasia, though not in the presence of Hp. We hypothesize that in humans, Fn gastric colonization may promote the continuation of gastric cancer development when Hp has been cleared. To test this hypothesis we will examine how Fn colonization impacts gastric preneoplastic progression using a mouse model where we can rapidly induce gastric metaplasia through conditional expression of KRAS in chief cells of the stomach (Aim 1). We hypothesize that Hp vs. Fn infection may elicit different host immune responses that could differentially contribute to disease progression. Thus, we will profile gastric and systemic inflammation driven by Fn vs. Hp in mice with metaplasia (Aim2). In Aim 3 we will utilize organoids derived from our mouse models to test phenotypic diversity upon different pathogen exposures. These aims will establish whether Fn can alter the preneoplastic trajectory of metaplasia in the stomach and develop tractable experimental models to mechanistically explore host and bacterial genes required. As well this overall strategy can be used to explore additional candidate cofactors for gastric cancer development.