代谢重塑介导肝肿瘤细胞与免疫微环境相互作用的机制与功能

肝癌是我国发病率前三位的癌症，它的治疗方案十分有限，急需发现新的治疗靶点。肿瘤免疫和代谢是近年来癌症研究和疗法创新的前沿，并且研究表明代谢对肿瘤免疫有显著调控作用。然而由于肝癌遗传背景的复杂性，如何塑造具有病理相关性的多样化原位肿瘤代谢重塑模型是一个难点。本实验室经过多年摸索建立了小鼠尾静脉转座子液态动力学注射方法，成功对肝细胞在体原位进行过表达、敲减、敲除等遗传修饰，并根据人肝癌突变谱建立了多样化的小鼠肝癌模型。本项目基于这一独特资源，平行分析不同基因型小鼠肝癌具有的代谢重塑特征和肿瘤免疫微环境表型。进而直接干扰代谢重塑，研究对肿瘤免疫微环境的影响和对小鼠肝癌发生发展的影响，并深入阐明相关机制。最后在人肝癌样品中验证这些机制的病理相关性。我们从遗传背景差异出发，系统性阐明差异化的肝细胞代谢重塑如何构建个性化的肿瘤免疫微环境。这些研究将为针对代谢和免疫的肝癌个性化治疗提供理论基础。

The incidence of liver cancer is ranked top 3 among all cancers in China. Unfortunately, for most patients, the cancer is too advanced with very limited treatments available. Therefore, new therapy based on insights into the mechanism of tumorigenesis of liver cancer is badly in need. Cancer metabolism and immunology are two frontiers of cancer research and are also the promising directions for new cancer therapies. Interestingly, studies demonstrated that tumor metabolism plays a significant role in the formation of the tumor immunological microenvironment. However, for liver cancer, this is difficult to investigate due to the lack of proper animal models as a result of the complicate genetic landscape of liver cancer. In the last few years we have established the hydrodynamic injection method in the lab, and have accomplished gene overexpression, knockdown, and CRISPR-mediated knockout in murine hepatocytes in vivo. We have also established an expanding library of liver cancer models based on the human liver cancer mutational landscape. In this project, we are going to analyze the metabolic reprogramming features and immunological microenvironments of tumors with different genotypes. Furthermore, we directly interfere the metabolic reprogramming process in vivo to investigate the impact on the immunological microenvironment and liver tumorigenesis. We then dissect the underlying cellular and molecular mechanisms. In addition, we investigate the relevance of our findings to human liver tumorigenesis by examining human liver cancer samples. In this project, we systematically investigate the role of metabolic reprogramming in mediating the effect of immunological microenvironment remodeling by differential genetic mutations. This work will point new directions for the development of novel metabolism- or cancer immunology-based personalized therapy for liver cancer.