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

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.

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。

肝癌是我国发病率前三位的癌症，其治疗方案十分有限，急需发现新的治疗靶点。肿瘤代谢和免疫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及其免疫微环境有显著调控作用。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。本项目提出根据人肝癌突变谱建立多样化的小鼠肝癌模型，并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。系统性阐明人肝癌基因突变不同组合如何通过差异化的肝细胞能量代谢重塑构建个性化的肿瘤免疫微环境，为针对代谢和免疫的肝癌个性化治疗提供理论基础。因此，本课题利用基于小鼠尾静脉液态高压注射的肝细胞体内基因编辑技术，以人肝癌突变谱为指导，成功建立了包含25种基因型的小鼠肝癌模型库（Science Advances, 2022）。该小鼠肝癌模型库资源以及多重基因编辑构建模型的方法体系为后续人肝癌基因突变不同组合对肝癌细胞能量代谢和免疫微环境的差异化重塑的机制研究奠定了基础。进一步对这些肿瘤的多组学分析揭示了与人肝癌对应的M1-M3三种分子分型，并阐明了由不同突变基因诱导的不同分型下肿瘤代谢和免疫微环境的特征，并揭示了M2型丙酮酸激酶Pkm2在代谢重塑和肝脏肿瘤进展中发挥基因型特异的作用。此外，我们系统性筛选线粒体蛋白鉴定了FUNDC2在肝肿瘤代谢重编程中的重要作用，揭示了FUNDC2通过抑制MFN1活性导致线粒体碎片化和代谢重编程并促进肝癌发生的机制，为肝癌精准治疗提供了新的潜在靶点（Nature Communications, 2022）。同时，我们发现细胞能量感受器AMPKgamma除了调控经典效应分子AMPKalpha，还调控磷酸酶PPP6C，并进而调控eEF2磷酸化，揭示了肝细胞能量水平耦合到蛋白质合成调控的关键机制（Molecular Cell, 2022）。