cMyc介导的脂类代谢重编程在调控肝癌免疫中的作用及机制

癌基因cMyc调控10-15%的基因，并在约50%的人类肿瘤中异常表达，在影响细胞增殖、分化、代谢和恶性转化中发挥重要的作用。我们前期报道了cMyc在调节细胞代谢中的重要作用（Nature 2009;EMBO J. 2015；Nat.Commu 2017），然而，目前尚不清楚cMyc是否通过代谢重编程来调节肿瘤免疫反应。在尚未发表的研究结果中，我们利用小鼠肝癌模型，发现cMyc影响肿瘤微环境内的脂类代谢，特别是胆汁酸代谢以及酮体代谢，并籍此影响免疫细胞功能。因此，本项目将利用小鼠肝癌模型及代谢组学分析等实验体系，系统研究cMyc介导的脂类代谢重编程在肝癌发生发展中的时空调控网络，并聚焦研究cMyc介导的胆汁酸代谢以及酮体代谢异常对肝癌免疫及肿瘤进程的影响。我们的研究结果将为肿瘤免疫代谢重编程的解析提供新的机制，并有可能为cMyc表达异常的临床肿瘤提供新的免疫治疗策略和手段。

cMyc regulates 10-15% of human genes and is deregulated in about 50% of human malignancies. cMyc is known to play important roles in regulating cell growth, differentiation, metabolism as well as transformation. We have documented previously various critical roles for cMyc in regulation of cellular metabolism（Nature, 2009; EMBO J 2015, Nat. Commu 2017). However, it's not clear whether cMyc influences tumor immunology via cellular metabolic reprogramming. In our unpublished data, we observed that cMyc significantly influences the catabolism of bile acids and ketone bodies in the tumor microenvironment and thereby affects the functions of immune cells. Thus, in this project, we will use various experimental systems such as mouse liver cancer models and metabolomics analysis to dissect the spatiotemporal networks for cMyc-mediated lipid metabolic reprogramming, bile acids and ketone body metabolism in particular, and its effects on tumor immunology and tumor progression. We will also explore new strategies to combine targeting cMyc-mediated lipid metabolic pathways for cancer immune therapy. We aim at illustrating new mechanisms for cancer progression and, hopefully, providing new strategies and rationales for cancer therapy, especially for malignancies with deregulated cMyc expression.