SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors  

作　　者：Xiaomin Wang Ziqi Chen Jun Xu Shuai Tang Nan An Lei Jiang Yixiang Zhang Shaoying Zhang Qingli Zhang Yanyan Shen Shijie Chen Xiaojing Lan Ting Wang Linhui Zhai Siyuwei Cao Siqi Guo Yingluo Liu Aiwei Bi Yuehong Chen Xiameng Gai Yichen Duan Ying Zheng Yixian Fu Yize Li Liang Yuan Linjiang Tong Kun Mo Mingcheng Wang Shu-Hai Lin Minjia Tan Cheng Luo Yi Chen Jia Liu Qiansen Zhang Leping Li Min Huang 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [2]University of Chinese Academy of Sciences,Beijing,China [3]Haihe Biopharma,Shanghai,China [4]Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences,School of Life Sciences,East China Normal University,Shanghai,China [5]Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [6]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,Jiangsu,China [7]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,Zhejiang,China [8]State Key Laboratory of Cellular Stress Biology,School of Life Sciences,National Institute for Data Science in Health and Medicine,Xiamen University,Xiamen,Fujian,China

出　　处：《Cell Research》2022年第7期638-658,共21页细胞研究（英文版）

基　　金：supported by the National Natural Science Foundation of China(81821005,91957126,81903640,91957120);the Program of Shanghai Academic Research Leader(20XD1424800).

摘　　要：Muta nt isocitrate dehydrog en ase 1(mlDH1)drives tumorigenesis via produci ng on cometabolite R-2-hydroxyglutarate(R-2-HG)across various tumor types.However,mlDHl in hibitors appear only effective in hematological tumors.The therapeutic ben efit in solid tumors remains elusive,likely due to the complex tumor microenvironment.In this study,we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis,conferring a therapeutic vulnerability in IDH1-mutant solid tumors.Mechanistically,SLC1 Alz a Na'-depe ndent glutamate tran sporter that is prefere ntially expressed in en dothelial cells,facilitates the in flux of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria.R-2-HG hijacks SLC1A1 to promote mitochondrial Na^(+)/Ca^(2+)exchange,which activates the mitochondrial respiratory chain and fuels vascular en dothelial cell migratio n in tumor an giogenesis.SLC1A1 deficiency in mice abolishes mlDHl-promoted tumor an giogenesis as well as the therapeutic benefit of mlDHl in hibitor in solid tumors.Moreover,we report that HH2301,a newly discovered mlDHl inhibitor,shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models.Together,we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular en dothelial cells,and dem on strate the therapeutic potential of mlDHl in hibitors in treating IDH1-muta nt solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.

关 键 词：IDH1 1A1 ANGIOGENESIS 

分 类 号：R730[医药卫生—肿瘤]