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

项目摘要 肠道微生物组和特定细菌物种的减少与CRC相关，并且这些数据 为CRC易感性、治疗反应和治疗方法提供了新的视角和见解。中央 癌症肠道微生物组研究的挑战是确定影响癌症的微生物的生物活性特征。 CRC易感性和进展。具核梭杆菌是一种革兰氏阴性厌氧细菌， 人类口腔微生物组的正常组成部分。然而，大量的研究表明，F。 与健康结肠组织相比，人结肠直肠腺瘤和CRC中富含Fn， 以及来自CRC个体的粪便中，并且肿瘤Fn富集与更差的总体存活相关， 无进展生存和化疗耐药性。我的实验室参与了检测腺瘤中Fn的研究， 结直肠癌，将梭菌的存在与各种结直肠癌风险因素相关联，并确定Fn如何起作用 使用临床前CRC模型，重点关注其与免疫细胞的相互作用。然而， 发现Fn促进CRC的机制。迄今为止，关于Fn毒力的大部分研究 CRC的作用机制主要集中在其粘附素和脂多糖。虽然此类研究表明 关于Fn的重要生物学，存在可能是Fn对CRC的贡献的基础的另外的机制。在这 更新建议，我们建立在我们的专业知识与Fn，微生物代谢和免疫学，以进一步 了解Fn对CRC的影响。具体而言，我们将研究三种生物活性的影响，Fn 结肠上皮和免疫细胞上的硫化氢产生、短链脂肪酸和Fic蛋白 肿瘤微环境的变化。在考虑由Fn使用但不限于Fn的更广泛的机制时， 我们希望将我们的发现的适用性扩展到Fn阴性CRC和其它恶性肿瘤。

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.