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: 10665786
• 负责人: Wendy S. Garrett
• 金额: $ 37.88万
• 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 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665786
• 关键词: Acetates; Adenosine Monophosphate; Amino Acids; Bacteria; Bacterial Adhesins; Bioenergetics; Biology; CDX2 gene; Cancer Model; Cell Proliferation; Cell physiology; Cells; Chemoresistance; Chemosensitization; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Adenoma; Colorectal Cancer; Cysteine; Data; Detection; Epithelium; Feces; Fusobacteria; Fusobacterium nucleatum; Genes; Genomics; Gnotobiotic; Gram-Negative Anaerobic Bacteria; Human; Hydrogen Sulfide; Immune; Immunology; Immunooncology; In Vitro; Individual; Lipid A; Lipids; LoxP-flanked allele; Malignant Neoplasms; Mediating; Meta-Analysis; Metabolism; Modeling; Modification; Mus; Myeloid Cells; NF-kappa B; Neoadjuvant Therapy; Organoids; Patients; Phosphotransferases; Polysaccharides; Population; Post-Translational Protein Processing; Pre-Clinical Model; Predisposition; Production; Progression-Free Survivals; Protein S; Proteins; Proteome; Rectal Cancer; Rectum; Relapse; Risk Factors; Role; Serine; Side; Spermidine Synthase; T-Lymphocyte; Technology; Testing; Therapeutic; Threonine; Tissues; Tryptophanase; Tyrosine; United States; Virulence; Volatile Fatty Acids; Work; adenoma; chemoradiation; colon carcinogenesis; colon tumorigenesis; colorectal cancer risk; gut microbiome; gut microbiota; hydroxyl group; in vivo; insight; lactate dehydrogenase A; microbial; microbiome research; microbiota; microorganism; mouse model; mutant; neoplastic cell; oral microbiome; pre-clinical; protein profiling; rectal; rho GTP-Binding Proteins; sulfhydration; treatment response; tumor; tumor microenvironment; tumor-immune system interactions

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.

项目概要 肠道微生物组和特定细菌种类的配置与 CRC 相关，此类数据 为结直肠癌的易感性、治疗反应和治疗方法提供新的视角和见解。一个中央 癌症肠道微生物组研究的挑战是定义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（Fusobacter nucleatum）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，现在大量研究表明 F. 与健康结肠组织相比，具核杆菌 (Fn) 在人类结直肠腺瘤和结直肠癌中富集，如 以及 CRC 患者的粪便中，并且肿瘤 Fn 富集与较差的总体生存率相关， 无进展生存和化疗耐药。我的实验室一直致力于检测腺瘤中 Fn 的研究 CRC，将梭杆菌的存在与各种 CRC 危险因素相关联，并确定 Fn 的作用 使用临床前 CRC 模型对 CRC 进行研究，重点关注其与免疫细胞的相互作用。然而，仍有许多工作要做 发现 Fn 对 CRC 的贡献机制。迄今为止，大部分关于 Fn 毒力的研究 CRC 的机制主要集中在其粘附素和脂质多糖。虽然此类研究表明 尽管 Fn 具有重要的生物学意义，但还有其他机制可能是 Fn 对 CRC 贡献的基础。在这个 更新提案中，我们利用 Fn、微生物代谢和免疫学方面的专业知识，进一步 了解 Fn 如何为 CRC 做​​出贡献。具体来说，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硫化氢的产生、短链脂肪酸和 Fic 蛋白 在不断变化的肿瘤微环境中。在考虑 Fn 使用但不限于 Fn 所使用的更广泛机制时， 我们希望将我们的研究结果的适用性扩展到 Fn 阴性结直肠癌和其他恶性肿瘤。

项目成果

Tumor necrosis factor α inhibits expression of the iron regulating hormone hepcidin in murine models of innate colitis.

• DOI: 10.1371/journal.pone.0038136
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Shanmugam NK;Ellenbogen S;Trebicka E;Wang L;Mukhopadhyay S;Lacy-Hulbert A;Gallini CA;Garrett WS;Cherayil BJ
• 通讯作者: Cherayil BJ

Nutrients, foods, and colorectal cancer prevention.

• DOI: 10.1053/j.gastro.2014.12.035
• 发表时间: 2015-05
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Song M;Garrett WS;Chan AT
• 通讯作者: Chan AT

Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression.

• DOI: 10.1080/19490976.2021.1987780
• 发表时间: 2021-01
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Brennan CA;Clay SL;Lavoie SL;Bae S;Lang JK;Fonseca-Pereira D;Rosinski KG;Ou N;Glickman JN;Garrett WS
• 通讯作者: Garrett WS

The reproductive tracts of two malaria vectors are populated by a core microbiome and by gender- and swarm-enriched microbial biomarkers.

• DOI: 10.1038/srep24207
• 发表时间: 2016-04-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Segata N;Baldini F;Pompon J;Garrett WS;Truong DT;Dabiré RK;Diabaté A;Levashina EA;Catteruccia F
• 通讯作者: Catteruccia F

Computational meta'omics for microbial community studies.

微生物社区研究的计算元杂志。

• DOI: 10.1038/msb.2013.22
• 发表时间: 2013-05-14
• 期刊: Molecular systems biology
• 影响因子: 9.9