肠道菌群影响结直肠癌发展和化疗敏感性的研究

Gut microbes are critical for normal functioning of homeostasis and health. Alterations of gut microbiota lead to cancer development. We have previously investigated gut microbiome dysbiosis in advanced CRC patients, and have identified microbiome genes that are enriched in different cancer stage of CRC patients. However, details about gut microbiota’s mechanistic contribution to the cancer development and chemotherapy sensitivity of CRC remain not well characterized. We show that CSN6 overexpression is frequently observed in CRC and associates with drug resistance and subsequent relapse of CRC patients. Importantly, CSN6 overexpression correlates with poor survival of CRC patients. CSN6 can induce stabilization of Myc, a master regulator of metabolism, which in turn may affect metabolism of microbes and results in alterations of microbiota. On the basis of these studies, we aim to investigate CSN6’s impact on microbiota alterations and subsequent effect in regulating CRC tumor growth and chemotherapy sensitivity through metagenomic sequencing. We will then characterize the regulation of gut microbiota changes on cancer development and drug resistance through fecal microbiome transplanation mouse model studies. We will determine the effect of characterized microbiome genes/metabolites on cancer development and drug resistance due to alterations of gut microbiota. The novelty of the proposal is that it will provide important insights into the potential signals and mechanisms behind microbiota reprogramming during cancer growth and developing drug resistance. The study will provide rational therapeutic strategy in targeting microbiota for treatment of CRC.

肠道菌群对维持肠道微生态和人类自身稳态及健康有重要作用，菌群的改变会导致肿瘤的发生和发展。申请人团队前期分析结直肠癌（CRC）和肠道菌群的关系，发现了一系列结直肠癌中富集的菌群。然而肠道菌群对CRC发展和化疗敏感性的影响及其作用机制尚有待研究。我们发现CSN6在CRC中高表达而且与CRC患者复发和化疗拮抗有关，CSN6高表达的CRC预后差。我们推测CSN6会通过Myc影响菌群，因此提出“CSN6相关肠道菌群影响CRC发展和化疗敏感性”的设想。本项目拟通过宏基因组测序筛选与CSN6相关肠癌发展和化疗敏感性相关菌群。利用小鼠菌群移植模型探究细菌影响肠道肿瘤发展和化疗敏感性的潜在机制。然后筛选相关肠道代谢物并在细胞和动物实验上进行验证。本课题旨在从“临床-动物-细胞”多角度分析肠道菌群与CSN6相关CRC发展和化疗敏感性间的关系及其潜在作用机制，为未来深化靶向肠道菌群诊治肠癌提供新的思路和方法。

肠道菌群对维持肠道微生态和人类自身稳态及健康有重要作用，菌群的改变会导致肿瘤的发生和发展。申请人团队通过本项目分析结直肠癌(CRC)和肠道菌群的关系，发现了一系列结直肠癌相关的菌群以及相关代谢异常分子标记物：第一，发现CSN6敲除小鼠可以改变肠道菌群，调控丝氨酸代谢促进肿瘤干性和化疗药耐药。第二，完成集体多位点肠道菌群和代谢组学联合动态分析，阐明肠道菌群动态过程与疾病发生发展呈现密切相关关系。第三，发现ILF3可以通过调控丝氨酸代谢促进结直肠癌恶性进展，其与肠道菌群关系密切。通过临床组织芯片分析，我们确证了ILF3与CSN6高表达与临床恶性预后相关。本项目为未来深化靶向肠道菌群诊治肠癌提供了新的思路和方法。