The role of Fusobacterium in colorectal cancer treatment, tumor ecology and chemotherapeutic efficacy

项目总结 苏珊·布尔曼博士是马修博士实验室的多学科博士后研究员 迈耶森在达纳-法伯癌症研究所和布罗德研究所工作。为了配合NCI的使命，她长期- 学期目标是领导一个独立的研究小组，研究肿瘤微生物区系在启动、进展、 和治疗人类胃肠道癌症，最终减少与癌症相关的死亡率和痛苦。 无偏见的基因组分析显示，在人的结肠中有丰富的核梭杆菌 相对于非癌性结直肠组织的癌症(CRC)。外源性核盘藻在动物体内的感染和 细胞模型支持它的促癌作用。此外，患有高水平结直肠癌的患者 梭杆菌在肿瘤中的存活率较差，这表明靶向梭杆菌可能提供了一种 创新治疗途径，增强化疗效果，改善疾病预后。 根据初步数据，这项提议将检验以下假设：(A)梭杆菌可以 作为治疗定植肿瘤的新靶点：抑制梭杆菌在梭杆菌中的生长 阳性患者来源的结直肠癌移植瘤将显著减少癌细胞的增殖和肿瘤 生长(AIM-1)，(B)核杆菌菌株具有不同的致癌能力和肿瘤分析 与梭杆菌在结直肠癌中的定位、共生微生物区系和宿主基因表达相关的生态学将 确定预测转移的“高危”标志(AIM-2)，最后，(C)核杆菌，最常见的 在结直肠癌中丰富的物种，直接调节/代谢常规的癌症化疗药物，并且 这种药物修饰会降低结肠癌的疗效和反应(AIM-3)。 布尔曼斯博士K99阶段将在迈耶森博士的主要指导下进行： 癌症基因组学和共同发现在结直肠腺癌中梭杆菌的丰富。 此外，由巴斯博士、德惠斯特博士、小野洋子博士和施赖伯博士组成的顾问委员会将监督她 科学进步，职业发展，并指导她过渡到终身教职的职位。这次培训 期间将使布尔曼博士在临床前癌症治疗模型、原位杂交方面获得经验 方法和分析化学。在指导的K99阶段，布尔曼博士将专注于确定 梭杆菌可以在这些人类肿瘤中做，以最大限度地发挥她的研究和翻译影响 过渡到独立R00阶段的基础，重点放在更机械化的研究上 《梭杆菌是如何做到这一点的》。布尔曼博士提出的逻辑和方法论实验将提供 对梭杆菌对结直肠癌的贡献的新见解，并支持她未来的独立研究。

PROJECT SUMMARY Dr. Susan Bullman is a multi-disciplinary postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at the Dana-Farber Cancer Institute and Broad Institute. In alignment with the NCI mission, her long- term goal is to lead an independent research group studying the role of tumor microbiota in initiation, progression, and treatment of human gastrointestinal cancers to ultimately reduce cancer-associated mortality and suffering. Unbiased genomic analyses have revealed an enrichment of Fusobacterium nucleatum, in human colorectal cancers (CRC) relative to non-cancerous colorectal tissues. Exogenous F. nucleatum infection in animal and cellular models has supported its cancer-promoting role. Additionally, patients with CRC that harbor high levels of Fusobacterium in their tumors show worse survival, suggesting that targeting Fusobacterium may provide a novel therapeutic route, potentiate the effects of chemotherapies, and improve disease prognosis. Stemming from preliminary data, this proposal will test the hypotheses that (A) Fusobacterium can be used as a novel therapeutic target in colonized tumors: inhibition of Fusobacterium growth in Fusobacterium- positive patient derived colorectal cancer xenografts will significantly reduce cancer cell proliferation and tumor growth (Aim-1), (B) F. nucleatum strains have varying pro-carcinogenic capabilities and analysis of tumor ecology relating to Fusobacterium’s localization, co-occurring microbiota, and host gene expression in CRC will identify “high-risk” signatures predictive of metastasis (Aim-2), and finally, (C) F. nucleatum, one of the most abundant species in CRC tumors, directly modulates/metabolizes routine cancer chemotherapeutics and that this drug modification contributes to diminished efficacy and response in colon cancers (Aim-3). Dr. Bullmans K99 phase will be performed under the primary mentorship of Dr. Meyerson: a leader in cancer genomics and co-discovered the enrichment of Fusobacterium in colorectal adenocarcinomas. Additionally, an advisory committee consisting of Drs. Bass, Dewhirst, Ogino and Schreiber will monitor her scientific progress, career development, and guide her transition to a tenure-track faculty position. This training period will allow Dr. Bullman to gain experience in pre-clinical cancer treatment models, in-situ hybridization approaches, and analytical chemistry. In the mentored K99 phase Dr. Bullman will focus on determining “what Fusobacterium can do” in these human tumors, to maximize the translational impact of her research and provide the foundation for transition to the independent R00 phase, with a focus on more mechanistic studies addressing “how Fusobacterium is doing it”. The logical and methodical experiments proposed by Dr. Bullman will provide novel insights into the contribution of Fusobacterium to CRC and support her future independent research.