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

项目摘要/摘要 肠道微生物组的特定配置与结直肠癌(CRC)有关，但肠道 微生物及其代谢产物及其与免疫系统的相互作用加强了结直肠癌的发生 人们对此仍然知之甚少。核梭杆菌是一种革兰氏阴性厌氧菌，属正常菌。 人类口腔微生物群的组成部分；然而，许多研究现在证明核盘藻 与健康的结肠组织相比，(FN)在人类结直肠腺瘤和结直肠癌中富含。而我们的团队 在该奖项的支持下参与了其中的几项研究；FN到底是如何促进结肠的 肿瘤发生机制尚未完全阐明。阐明纤维连接蛋白形成结肠肿瘤的机制 微环境将为开始多管齐下地使用FN作为 结直肠癌防治中的诊疗靶点。根据我们第一次的调查结果 对于这次竞争性的R01续订，我们提出了FN是一个 致癌微生物通过其对结直肠癌肿瘤微生物区系的影响，通过其肿瘤代谢产物，以及通过 它与肿瘤内免疫细胞的直接相互作用促进了结直肠癌的生长和发展。 利用我们在FN、元组学和鼠标模型方面的知识和专业知识，我们将解决FN如何 通过其短链脂肪酸，增强其作为肿瘤菌的作用，促进结直肠癌的发生 (肿瘤代谢物)及其在肿瘤免疫微环境中的相互作用(肿瘤免疫学)。

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).