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

项目总结 肠道微生物群和特定细菌种类的配置与结直肠癌有关，这样的数据 为结直肠癌的易感性、治疗反应和治疗提供新的视角和见解。一个中环 癌症肠道微生物组研究的挑战是确定影响肠道微生物的生物活性特征 结直肠癌的易感性和进展。核梭杆菌是一种革兰氏阴性厌氧菌。 人类口腔微生物群的正常组成部分。然而，许多研究现在证明F. 与健康的结肠组织相比，结直肠腺瘤和结直肠癌组织中富含核酸盐(FN)，如 结直肠癌患者的粪便中也是如此，肿瘤中FN的丰富与较差的总体生存率相关， 无进展生存和化疗耐药。我的实验室参与了检测腺瘤中FN的研究 结直肠癌，融合细菌的存在与各种结直肠癌危险因素的相关性，并确定FN可能如何起作用 使用临床前结直肠癌模型，重点研究其与免疫细胞的相互作用。然而，还有很多事情要做 了解FN对CRC的贡献机制。到目前为止，关于FN毒力的大部分研究 结直肠癌的作用机制主要集中在其粘附素和脂多糖上。虽然这些研究揭示了 尽管FN具有重要的生物学意义，但FN在结直肠癌中的作用可能还有其他机制。在这 更新建议，我们在FN、微生物新陈代谢和免疫学方面的专业知识基础上，进一步 了解国民阵线如何为儿童权利委员会作出贡献。具体地说，我们将调查三种生物活动的影响，FN 结肠上皮和免疫细胞产生硫化氢、短链脂肪酸和Fic蛋白 在不断演变的肿瘤微环境中。在考虑由FN使用但不排他于FN的更广泛机制时， 我们希望将我们的发现扩展到FN阴性的结直肠癌和其他恶性肿瘤。

PROJECT SUMMARY Configurations of the gut microbiome and specific bacterial species are associated with CRC, and such data provide fresh perspectives and insights into CRC susceptibility, response to therapy, and therapeutics. A central challenge of cancer gut microbiome studies is to define the bioactive features of micro-organisms that influence CRC susceptibility and progression. 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, as well as in stool from individuals with CRC, and that tumoral Fn-enrichment correlates with worse overall-survival, progress-free survival and chemoresistance. My lab has been involved in studies detecting Fn in adenomas and CRC, correlating fusobacterial presence with various CRC risk factors, and determining how Fn may contribute to CRC using preclinical CRC models with a focus on its interactions with immune cells. Yet, much remains to discover about the mechanisms by which Fn contributes to CRC. To date, the bulk of studies on Fn virulence mechanisms in CRC have focused on its adhesins and its lipid polysaccharide. While such studies have revealed important biology about Fn, there are additional mechanisms that may underlie Fn's contribution to CRC. In this renewal proposal, we build upon our expertise with Fn, microbial metabolism, and immunology to further understanding of how Fn contributes to CRC. Specifically, we will investigate the effects of three bioactivities, Fn hydrogen sulfide production, short-chain fatty acids and Fic proteins, on the colonic epithelium and immune cells in the evolving tumor microenvironment. In considering broader mechanisms used by but not exclusive to Fn, we hope to extend the applicability of our findings to Fn-negative CRC and other malignancies.