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

项目摘要 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 Meyerson在Dana-Farber癌症研究所和布罗德研究所。为了配合NCI的使命，她的长期- 长期目标是领导一个独立的研究小组，研究肿瘤微生物群在肿瘤发生，发展， 和治疗人胃肠道癌症，以最终降低癌症相关的死亡率和痛苦。 无偏倚的基因组分析揭示了人类结直肠癌中具核梭杆菌的富集 癌症（CRC）相对于非癌性结肠直肠组织的差异。外源F.动物核感染， 细胞模型支持其促进癌症的作用。此外，具有高水平的CRC患者 的梭杆菌在他们的肿瘤中显示出更差的存活率，这表明靶向梭杆菌可能提供一种治疗方法， 新的治疗途径，增强化疗效果，改善疾病预后。 从初步数据出发，该建议将测试以下假设：（A）梭杆菌可以是 作为一种新的治疗靶点用于定殖肿瘤：抑制梭杆菌属中的梭杆菌生长- 阳性患者来源的结直肠癌异种移植物将显着减少癌细胞增殖和肿瘤 生长（Aim-1），（B）F.有核菌株具有不同的促癌能力和肿瘤分析 与结直肠癌中梭杆菌的定位、共存微生物群和宿主基因表达相关的生态学将 鉴定预测转移的“高风险”特征（Aim-2），以及最后，（C）F. nucleatum，一个最重要的 在CRC肿瘤中的丰富种类，直接调节/代谢常规癌症化疗药物， 这种药物修饰有助于降低结肠癌的疗效和反应（Aim-3）。 Bullmans博士的K99阶段将在Meyerson博士的主要指导下进行：Meyerson博士是 癌症基因组学，并共同发现了结直肠腺癌中梭杆菌属的富集。 此外，一个由Bass博士、Dewhirst博士、Ogino博士和Schreiber博士组成的咨询委员会将对她进行监测。 科学进步，职业发展，并引导她过渡到终身教职。本次培训 期间将使布尔曼博士获得经验，在临床前癌症治疗模式，原位杂交 方法和分析化学。在指导K99阶段，Bullman博士将专注于确定“什么 梭杆菌可以做”在这些人类肿瘤，以最大限度地提高她的研究的翻译影响，并提供 过渡到独立R 00阶段的基础，重点是更多的机制研究， “梭杆菌是如何做到的”布尔曼博士提出的逻辑和方法实验将提供 她对梭杆菌对CRC的贡献提出了新的见解，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.