Gastrointestinal microbiota interactions modulating gastric cancer progression

项目总结 胃癌是全球第四大死因，80%的病例是由幽门螺杆菌引起的 幽门螺杆菌(HP)感染。幽门螺杆菌如何促进胃癌的确切机制尚不清楚。肠道 类型胃癌是最常见的组织学类型，被认为是由一系列组织变化引起的。 由幽门螺杆菌引起的慢性炎症引发，首先是产酸的壁细胞(胃 萎缩)和可能导致异型增生和胃癌的化生细胞的出现。细菌 分泌毒素CagA等因素以及吸烟和饮食等宿主行为因素有助于 有患胃癌的风险。然而，只有1-2%的感染幽门螺杆菌的人最终会患上胃癌和 在胃癌病例中，超过一半的人在确诊时已经失去了幽门螺杆菌的定植。这个 与化生和异型增生相关的组织变化(酸减少、粘蛋白表达改变和 糖基化作用)有利于口腔细菌在胃中生长。因此，包括其他因素在内的其他因素 微生物，可能对胃癌的病因学有贡献。 核梭杆菌(Fn)是口腔微生物区系中的一员，但也与结直肠癌有关 通过对人类肿瘤的微生物测序和在异种移植和 转基因小鼠模型。最近，FN在进展期胃病变和胃中被发现 癌症，与惠普显然是相互排斥的关系。我们发现，太平洋地区19%的患者 西北(PNW)胃癌队列有(FN)胃感染。在小鼠中，我们的初步数据显示Fn是一种 健康胃的糟糕殖民者，但在KRAS驱动的背景下强有力地殖民了胃 化生，尽管不存在幽门螺杆菌。我们假设在人类中，FN在胃中的定植 当幽门螺杆菌被清除后，可能会促进胃癌的继续发展。为了测试这一点 假设我们将使用小鼠研究FN定植对胃癌前病变进展的影响 我们可以通过KRAS在主细胞中的条件表达快速诱导胃化生的模型 胃部(目标1)。我们推测Hp和Fn感染可能会引起不同的宿主免疫反应， 可能在不同程度上促进疾病的进展。因此，我们将描述胃和全身炎症。 在化生小鼠(AIM2)中，由FN和Hp驱动。在目标3中，我们将使用从我们的老鼠身上提取的有机化合物 测试不同病原体暴露的表型多样性的模型。这些目标将确定国民阵线是否 可以改变胃化生的癌前轨迹，开发出易于处理的实验模型 以机械方式探索所需的宿主和细菌基因。此外，这一总体战略还可以用于 探索胃癌发生的其他候选辅助因素。

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.