Interactions Between the Microbiota and Helicobacter pylori in Gastric Carcinogenesis

摘要 本多份Pl R01是针对NCI FOA PAR-20-062共同感染和癌症而提交的，包括 2个经验丰富的、协作的、在微生物致癌方面具有互补专业知识的个人(Richard Peek和 詹姆斯·福克斯)。幽门螺杆菌是已知的患胃腺癌的最高风险。然而，COPIS的研究 其他人已经证明，胃微生物区系群与幽门螺杆菌协同影响癌症风险。 我们完全可以接触到哥伦比亚的一个独特的纵向预期人类队列，那里的胃 腺癌和幽门螺杆菌感染是地方性疾病。可获得完整的临床、内窥镜和组织学数据 在基线和每隔一段时间随访26年，包括用于微生物区系分析的冷冻胃组织 以及来自20年和26年时间点的培养，这些人要么是组织学进步的，要么是 保持稳定，为确定疾病机制提供了独特的机会。我们还可以访问 从斯坦福大学有或没有癌前病变的患者身上前瞻性地获取胃组织，使我们能够 将这些研究扩展到美国人口中。我们的实验室开发出的模型可以很好地概括 在幽门螺杆菌和微生物群的背景下确定致癌机制的胃壁生态位。Dr。 福克斯利用无菌(GF)INS-GAS小鼠证明：1)幽门螺杆菌可加速小鼠的癌症发生 与GF小鼠相比，拥有胃微生物区系，以及2)具有不同代表的细菌的定植 在癌症风险较高的人群和癌症风险较低的人群中，幽门螺杆菌改变了诱导胃损伤的能力。Peek博士已经 发展复杂的初级胃样：巨噬细胞：T细胞系统以证明幽门螺杆菌驱动致癌 以细胞和菌株特有的方式进行信号传递，而非H。幽门螺杆菌胃种成功地定植了这些 模特们。总体而言，我们的科学范围、可用的资源包括尖端代谢组学，以及 创新的模型系统将使我们能够充分解决进展为胃癌是 不仅受幽门螺杆菌毒力成分的影响，而且还受与幽门螺杆菌成员的长期相互作用的影响 胃微生物区系。它可以调节免疫反应。我们将通过这些目标来解决这一假设。 目标1：确定和定义胃部微生物区系的成分，这些人是否有进展 全基因组鸟枪法(WMS)测定胃癌 目的2：利用创新的体外系统来确定胃微生物区系的致癌潜力和 优先考虑更明确的胃癌体内研究的候选对象 目的3：利用新的无菌啮齿动物模型和代谢组学来确定高优先胃病的因果关系 与胃龛内疾病进展相关的微生物区系种类和相应的免疫反应

Summary This multi-Pl R01 is submitted in response to NCI FOA PAR-20-062 Co-infection and Cancer and includes 2 seasoned, collaborative Pis with complementary expertise in microbial carcinogenesis (Richard Peek and James Fox). H. pylori confers the highest known risk for gastric adenocarcinoma. However, studies by the CoPis and others have demonstrated that gastric microbiota populations affect cancer risk in synergy with H. pylori. We have full access to a unique longitudinal, prospective human cohort in Colombia where gastric adenocarcinoma and H. pylori infections are endemic. Full clinical, endoscopic, and histologic data are available at baseline and at each interval follow-up out to 26 years, including frozen gastric tissue for microbiota analysis and culture from the 20- and 26-year timepoints from persons who either progressed histologically or remained stable, providing a unique opportunity to define disease mechanisms. We also have access to prospectively obtained gastric tissue from patients at Stanford with or without premalignant lesions, allowing us to extend these studies into a US population. Our laboratories have developed models that closely recapitulate the gastric niche to define mechanisms of carcinogenesis within the context of H. pylori and the microbiota. Dr. Fox has utilized germ-free (GF) INS-GAS mice to demonstrate 1) H. pylori accelerates carcinogenesis in mice harboring a gastric microbiota compared to GF mice, and 2) colonization with bacteria differentially represented in high vs. low cancer risk populations modifies the ability of H. pylori to induce gastric injury. Dr. Peek has developed complex primary gastroid:macrophage:T cell systems to demonstrate that H. pylori drives oncogenic signaling in a cell- and strain-specific manner and that non-H. pylori gastric species successfully colonize these models. Collectively, our scientific scope, available resources including cutting-edge metabolomics, and innovative model systems will allow us to fully address the hypothesis that progression to gastric cancer is influenced not only by H. pylori virulence constituents, but also by prolonged interactions with members of the gastric microbiota. which can modulate immune responses. We will address this hypothesis via these Aims. Aim 1: Identify and define components of the gastric microbiota in persons who did or did not progress towards gastric cancer using Whole Metagenome Shotgun (WMS} sequencing Aim 2: Utilize innovative ex vivo systems to define the carcinogenic potential of gastric microbiota species and prioritize candidates for more definitive in vivo studies of gastric cancer Aim 3: Utilize novel germ-free rodent models and metabolomics to define causality of high priority gastric microbiota species and corresponding immune responses linked to disease progression within the gastric niche