MTA1相关细胞因子介导的肿瘤细胞—微环境交互作用在肿瘤转移过程中的效应和机制研究

Cancer metastasis is developed through the interaction between cancer cells and microenvironment, among which cytokine network plays a very importment part. We found clues that metastasis-associated gene 1 (MTA1)is a new cancer microenvironment modulator, responsible for the expression regulation of a large amount of cytokines, stiring the fibroblasts in the metastatic sites into those with cancer-associated fibroblasts (CAFs) phenotypes. Based on our pilot study, we will investigate the MTA1-modulated cytokine interaction between cancer cells and fibroblasts through the combining of high pressure liquid chromatography and mass spectrum techniques.we will identify the key cytokines playing a joint role in the cancer metastasis microenvironment, The results will be verified with various models at the molecular biological and cellular levels as well as in cancer samples from patients and tumor-bearing mice model, establishing a cytokines feedback loop between cancers and CAFs which is regulated by MTA1. This project will deepen the understanding on cancer metastasis microenvironment and start a new research area of MTA1 function, which contributes novalty to the medical sciences both theoratically and practically.

肿瘤转移是肿瘤细胞与微环境相互作用的结果。细胞因子网络在肿瘤微环境调控中发挥重要作用。我们的研究显示转移相关基因1(MTA1)是一个新的肿瘤微环境调控因子，调控大量肿瘤微环境相关细胞因子的表达，刺激成纤维细胞转化为肿瘤相关成纤维细胞（CAFs）表型。本课题在前期工作基础上，以MTA1调控转移微环境中肿瘤细胞—成纤维细胞之间的细胞因子交互作用为主线，通过高效液相色谱与质谱技术联用的方法，鉴定MTA1参与结肠癌肝转移微环境调控的关键细胞因子，并在细胞生物学、分子生物学、临床肿瘤标本、结肠癌肝转移动物模型、基因修饰动物等多层次进行验证，最终建立MTA1调控肿瘤微环境中“肿瘤细胞-CAFs”之间的细胞因子环路模型。本研究的将进一步深化对肿瘤转移微环境调控机制的认识，同时开辟了新的MTA1功能研究领域，具有较高的理论创新性和潜在应用价值。

肿瘤转移是一个多步骤、多环节的过程，与周围间质内的环境密切相关。转移相关基因1（MTA1）是一个在肿瘤转移过程中表达上调的基因，已有研究报道它促进肿瘤的转移，但MTA1是否在转移微环境中调控了肿瘤细胞与其他间质细胞制建的信号调控功能，尚无报道。在本研究中，我们在结肠癌患者的细胞因子芯片与TCGA数据中筛选与转移及生存相关的细胞因子，构建相关因子的crispr敲除和过表达文库，筛选体内外转移相关细胞因子，分析结肠癌细胞来源的细胞因子对巨噬细胞活性的影响，以及巨噬细胞与结肠癌细胞共注射对肿瘤细胞肝转移的影响，探究MTA1驱动的癌症转移对EMT的诱导机制。本研究发现的结肠癌细胞与局部CAFs之间的相关性，为进一步研究提供了理论基础，具有重要的科学意义和应用前景。