Mutant isocitrate dehydrogenase 1(mIDH1)drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate(R-2-HG)across various tumor types.However,mIDH1 inhibitors appear only effective in hematological tumors.The therapeutic benefit 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,SLC1A1,a Na+-dependent glutamate transporter that is preferentially expressed in endothelial cells,facilitates the influx 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+/Ca2+exchange,which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis.SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors.Moreover,we report that HH2301,a newly discovered mIDH1 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 endothelial cells,and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.

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

State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China;University of Chinese Academy of Sciences,Beijing,China;Haihe Biopharma,Shanghai,China;Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences,School of Life Sciences,East China Normal University,Shanghai,China;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China;School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,Jiangsu,China;School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,Zhejiang,China;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

细胞研究（英文版）

[1]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-.SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors)[J].细胞研究（英文版）,2022(07):638-658

SLC1A1,hydroxyglutarate,mIDH1,oncometabolite,remodels,hijacks,Ca2+exchange,HH2301

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