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: 9307232
• 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/9307232
• 关键词: Address; Affect; Amino Acids; Anaerobic Bacteria; ApcMin/+ mice; Award; Bacteria; Cancer Etiology; Cells; Cessation of life; Characteristics; Clinical; Colonic Adenoma; Colonic Neoplasms; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Diagnostic; Effectiveness; Epithelium; Fermentation; Funding; Fusobacterium nucleatum; Genetic Determinism; Gnotobiotic; Gram-Negative Anaerobic Bacteria; Growth; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; In Vitro; Individual; Infiltration; Investigation; Knowledge; Libraries; Lymphoid Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Microbe; Mono-S; Mus; Myelogenous; Organism; Oxygen; Patients; Pre-Clinical Model; Production; Regulatory T-Lymphocyte; Renal Cell Carcinoma; Role; Shapes; Structure; Subgroup; Testing; Therapeutic; Tissues; Tumor Immunity; Volatile Fatty Acids; base; cancer immunotherapy; cancer therapy; colon cancer patients; colon carcinogenesis; colorectal cancer prevention; fitness; global health; gut microbiome; immune checkpoint; in vivo; insight; melanoma; microbial; microbial community; microbial host; microbiota; molecular subtypes; mouse model; mutant; neoplastic; non-smoker; oral microbiome; permissiveness; receptor; success; therapeutic target; tumor; tumor microenvironment; 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/文摘