代谢在肠癌干细胞分裂中的不对称分布及机制的研究

肿瘤干细胞可以进行不对称分裂产生一个干细胞和一个分化的细胞。肿瘤干细胞和分化细胞的代谢不同，然而二者代谢的差异何时、怎样建立还很不清楚。申请人长期从事干细胞不对称分裂和肿瘤代谢的研究，并发现磷酸甘油酸脱氢酶（PHGDH）在肠癌干细胞分裂中不对称的分布在干细胞中；敲低PHGDH的表达，能够有效抑制肠癌干细胞的自我更新。本项目中，申请人将：（1）进一步整合代谢组学和转录组学，系统研究肠癌干细胞和分化细胞间的代谢酶和代谢的差异；（2）系统鉴定在肠癌干细胞分裂中不对称分布的代谢酶和代谢通路及其调控机理；（3）研究代谢酶对干细胞命运、肠癌发生发展的影响；（4）筛选靶向代谢酶的小分子药物，通过消除干细胞，治疗肠癌。本项目将首次发现代谢酶在肠癌干细胞不对称分裂过程中不对称的分布在干细胞中，建立肠癌干细胞和分化细胞间的代谢差异。本项目还将筛选靶向关键代谢酶的有效的小分子药物，通过消除肠癌干细胞，治疗肠癌。

Cancer stem cells can undergo asymmetric division to produce a stem cell and a differentiated cell. Cancer stem cells and differentiated cells have different metabolisms, but it is not clear when and how the metabolic differences are established. The applicant has worked on asymmetric division of stem cells and cancer metabolism for a long time and found that phosphoglycerate dehydrogenase (PHGDH) in the division of colorectal cancer stem cells was asymmetrically distributed in stem cells during colon cancer stem cell asymmetric division. Knockdown of PHGDH can effectively inhibit colon cancer stem cell self-renewal.In this project, the applicants will :(1) further integrate metabolomics and transcriptome to systematically study the differences in metabolic enzymes and metabolism between colon cancer stem cells and differentiated cells;(2) systematically identify metabolic enzymes and pathways that are asymmetrically distributed during colon cancer stem cell asymmetrical division and the regulatory mechanisms;(3) study the effects of metabolic enzymes on the fate of stem cells and the development of colorectal cancer;(4) screen small-molecule drugs against metabolic enzymes to treat colon cancer by eliminating stem cells. In this project, metabolic enzymes were firstly found to be asymmetrically distributed in the stem cells during the asymmetric division of colon cancer stem cells. The project will also screen effective small molecule drugs against key metabolic enzymes to treat tumors by eliminating colorectal cancer stem cells.