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.