Colorectal carcinogenesis and Fusobacterium nucleatum: oncomicrobe, oncometabolites, and oncoimmunology

结直肠癌发生和具核梭杆菌：致癌微生物、致癌代谢物和肿瘤免疫学

• 批准号: 10207518
• 负责人: Wendy S. Garrett
• 金额: $ 34.67万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-18 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207518
• 关键词: Address; Affect; Amino Acids; Anaerobic Bacteria; ApcMin/+ mice; Award; Bacteria; Cancer Etiology; Cessation of life; Characteristics; Clinical; Colonic Adenoma; Colonic Neoplasms; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Diagnostic; Effectiveness; Epithelial; Fermentation; Funding; Fusobacterium nucleatum; Genetic Determinism; Gnotobiotic; Gram-Negative Anaerobic Bacteria; Growth; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunooncology; In Vitro; Individual; Infiltration; Investigation; Knowledge; Libraries; Lymphoid Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Microbe; Mus; Myelogenous; Organism; Oxygen; Patients; Pre-Clinical Model; Production; Regulatory T-Lymphocyte; Renal Cell Carcinoma; Role; Shapes; Structure; Subgroup; Testing; Therapeutic; Tissues; Tumor Immunity; Tumor-infiltrating immune cells; Volatile Fatty Acids; base; cancer immunotherapy; cancer therapy; colon cancer patients; colon carcinogenesis; colorectal cancer prevention; fitness; global health; gut microbes; gut microbiome; immune checkpoint; in vivo; insight; melanoma; microbial; microbial community; microbial host; microbiota; molecular subtypes; mouse model; mutant; neoplastic; non-smoker; oral microbiome; patient subsets; receptor; success; therapeutic target; tumor; tumor microbiota; tumor microenvironment; tumor-immune system interactions; tumorigenesis

PROJECT SUMMARY/ABSTRACT Specific configurations of the gut microbiome have been associated with colorectal cancer (CRC), but how gut microbes, their metabolites, and their interactions with the immune system potentiate colorectal carcinogenesis remains poorly understood. Fusobacterium nucleatum, a Gram-negative anaerobic bacterium, is a normal constituent of the human oral microbiome; however, numerous studies now demonstrate that F. nucleatum (Fn) is enriched in human colorectal adenomas and CRC compared to healthy colonic tissues. While our group has been involved in several of these studies under the aegis of this award; exactly how Fn promotes colonic tumorigenesis has not been fully elucidated. Clarifying the mechanisms by which Fn shapes the colonic tumor microenvironment will provide important insight for embarking on a multipronged approach to use Fn as a diagnostic and therapeutic target in CRC prevention and treatment. Based on the findings from our first funding cycle for this competitive R01 renewal, we formulate the overarching hypothesis that Fn is an oncomicrobe that through its effects on the CRC tumoral microbiota, via its oncometabolites, and by its direct interactions with intratumoral immune cells contributes to CRC growth and progression. Leveraging our knowledge and expertise with Fn, meta'omics, and mouse models, we will address how Fn potentiates colorectal carcinogenesis in its role as an oncomicrobe, via its short-chain fatty acids (oncometabolites), and in its interactions within the tumor immune microenvironment (oncoimmunology).

项目总结/摘要 肠道微生物组的特定结构与结直肠癌（CRC）相关，但肠道微生物组如何与结直肠癌（CRC）相关？ 微生物、其代谢产物及其与免疫系统的相互作用可增强结直肠癌的发生 仍然知之甚少。具核梭杆菌是一种革兰氏阴性厌氧菌， 人类口腔微生物组的组成部分;然而，许多研究现在表明，F.具核 (Fn)与健康结肠组织相比，在人结肠直肠腺瘤和CRC中富集。当我们的团队 在这个奖项的支持下，我参与了其中的几项研究;确切地说，Fn是如何促进结肠的 肿瘤发生尚未完全阐明。阐明Fn形成结肠肿瘤的机制 微环境将提供重要的见解，为着手采取多管齐下的方法，使用Fn作为一个 诊断和治疗目标的CRC预防和治疗。根据我们第一次 对于这种竞争性R 01更新的资金周期，我们制定了总体假设，即Fn是一个 肿瘤微生物，通过其对CRC肿瘤微生物群的影响，通过其肿瘤代谢， 它与肿瘤内免疫细胞的直接相互作用有助于CRC的生长和进展。 利用我们在Fn、Meta组学和小鼠模型方面的知识和专业知识，我们将解决Fn 作为一种致癌微生物，通过其短链脂肪酸， （肿瘤免疫学），以及其在肿瘤免疫微环境中的相互作用（肿瘤免疫学）。