不同亚型巨噬细胞对肿瘤细胞上皮间质转化及转移的影响和机制研究

The domination of most cancer-related deaths is caused by metastasis, which is tightly impacted by tumor microenvironment. Macrophage is one of the most abundant type of cell found in microenvironment of solid tumors, especially lethal metastatic tumors. Clinical studies have evidently demonstrated that the high number of macrophages in tumor correlates with poor survival and prognosis in most solid tumors such as breast, gastric, oral, ovarian, bladder and thyroid cancers. Macrophage supports tumor progression, promotes angiogenesis and tumor spreading at distant sites and creates an immunosuppressive environment. However, the underlying mechanism is not clear. Based on our previous research on the role of both hypoxia and inflammation in promoting EMT, which are both associated with macrophage, we focus on the mechanism of EMT and metastasis promoted by macrophage in this project. In this proposal, the applicant plans to induce different subtypes of macrophage; determine their specific roles in tumor growth, survival, EMT and metastasis; identify the key driver pathways behind. This study will provide a mechanistic basis for developing future therapies and will provide novel targets for new chemotherapies. Combination of drugs that block tumor-promacrophages with drugs like PD1/PD-L1 antibodies that re-activate T-cell will provide more promising cancer treatment approaches in future.

肿瘤转移是造成癌症相关死亡的主要因素，其与肿瘤微环境密切相关。巨噬细胞是多数恶性肿瘤微环境中的主要组成部分。临床数据表明，巨噬细胞的密度与肺癌、肝癌、肾癌、乳腺癌等预后不良密切相关。巨噬细胞促进新生血管的形成、肿瘤细胞的侵袭、迁移、血管内渗以及在肿瘤转移发生位点刺激肿瘤细胞的血管外渗和持续生长。但是其是其发挥作用的详细机制还没有很深入的了解。基于之前申请人研究关注的肿瘤细胞EMT促进作用的低氧和炎症因子等肿瘤微环境都与巨噬细胞的参与密切相关，申请人设计本项目课题直接关注巨噬细胞调控肿瘤细胞EMT的功能机制。申请人将从诱导不同巨噬细胞亚型出发，研究不同巨噬细胞亚型对肿瘤细胞生长、存活、转移的作用影响，对其发挥作用的驱动通路和分子机制进行深入的研究，为肿瘤治疗提供新的潜在药物靶点。阻断巨噬细胞促肿瘤作用的药物与解除T细胞抑制状态的PD1/PD-L1等药物的联合应用可能会具有更好的抗肿瘤前景。

巨噬细胞在肿瘤发生发展中发挥着至关重要的作用，但是其发挥作用的详细机制还没有很深入的了解。我们从巨噬细胞分化模型的建立、诱导肿瘤细胞转移模型、及蛋白质修饰组学分析鉴定出了24个蛋白质翻译后修饰的蛋白质可能参与肿瘤转移，通过点突变、特异性抗体等进一步对这13个蛋白进行验证，并通过如去修饰药物或Crispr/cas9敲除，过表达等技术探索关键修饰功能酶在EMT中的作用及其作用机制，采用如co-IP, CHIP等技术寻找此关键修饰功能酶上下游调控因子，鉴定关键的驱动通路。为将来扰乱肿瘤细胞与巨噬细胞直接的正反馈回路提供了靶点。