申请人的研究主要以肿瘤代谢调控为切入点，解析癌症的发生、发展的分子基础。在美期间，申请人的工作主要阐述了丙酮酸激酶M2亚型（PKM2）在癌症的发生中的作用及机制，并发表第一作者研究论文4篇：（1）发现了代谢酶PKM2作为转录因子Coactivator功能(Nature）；（2）发现了PKM2作为组蛋白激酶调控表观遗传的功能(Cell）；（3）揭示了PKM2转运入核机制（Nature Cell Biology）；（4）阐述了PKM2表达调控机制（Molecular Cell）。研究成果曾多次被知名期刊专题报道。期间，申请人获Odyssey Fellowship和几个癌症研究基金资助，以及多次重要科研奖励，并成为奥德赛冠名学者。申请人自2013 年6月在中科院生化与细胞所建立独立实验室以来，继续从事癌症发生及放化疗耐受的分子机制研究，目前已经建立了相关的研究系统并取得若干重要的研究进展。

More and more studies indicated the expression of metabolic enzyme was upregulated in many tumor cells, and that oncogene functions by regulating the expression of metabolic enzyme. However, the roles of unregulated cancer metabolism in tumorigenesis and radio/chemo-resistance remain unclear. The research interest of the applicant is to decipher the molecular basis of tumorigenesis by studying the regulation of cancer metabolism. During the period in U.S, the work of the applicant mainly demonstrated the roles and underlying mechanisms of pyruvate kinase M2 isoform (PKM2) in EGFR-promoted tumorigenesis. The applicant has published 4 first-author papers in prestigious journals. The major contributions include: (1) Discovered the new function of PKM2 as a transcription factor co-activator (Nature, 2011); (2) Discovered the new function of PKM2 as a protein kinase to regulate epigenetics (Cell, 2012); (3) Revealed the detailed mechanisms of PKM2 nuclear translocation (Nature Cell Biology, 2013); (4) Demonstrated the regulation of PKM2 expression mediated by EGFR-PKC-NF-kB signal cascade. These findings were highlighted by many prestigious journals. The applicant was funded by MD Anderson Cancer Center-Odyssey fellowship, The Harold C. and Mary L. Daily Endowment Fund，The Thomas H. and Mayme P. Scott Fellowship in Cancer Research，and Lupe C. Garcia Fellowship in Cancer Research, and awarded several honors, and selected as Odyssey Fellow. Since an independent lab was created in the Institute of Biochemistry and Cell Biology in June 2013, the applicant continued to decipher the molecular basis of tumorigenesis and chemo/radio-resistance and made several critical progress.

大量研究表明肿瘤细胞有着与正常细胞截然不同的代谢表型，这些代谢上的异常在癌症发生发展过程中起着至关重要的作用。然而，这些异常的代谢通路如何支撑肿瘤细胞的各种行为，及在肿瘤发生发展过程中又如何被调控，目前还知之甚少。本项目围绕糖酵解通路中两个关键酶：丙酮酸激酶PKM2和磷酸果糖激酶PFKM，着重阐述了1）PKM2通过转运至线粒体直接磷酸化BCL2，并维持其蛋白稳定性，进而维持了肿瘤细胞在高氧化应激条件下的存活；2）葡萄糖匮乏条件下，PFKM发生单泛素化的去除，并转运至细胞核内与转录因子c-MYC相互作用，增强了c-MYC的转录激活能力，进而上调了脂肪酸氧化相关基因的表达，最终维持了肿瘤细胞在葡萄糖匮乏条件下的存活。研究结果1）首次发现PKM2的线粒体定位，并揭示了线粒体定位的PKM2同样具备蛋白激酶活力，此外BCL2 T69磷酸化水平与胶质瘤病人预后及肿瘤分级密切相关；2）首次发现PFKM的细胞核转运，并通过调控经典转录因子c-MYC改变肿瘤细胞能量获取来源，进而支撑肿瘤细胞在营养匮乏条件下的存活。