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

Abstract

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.

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Fig. 1: R-2-HG influx promotes vascular endothelial cell migration.
Fig. 2: SLC1A1-dependent R-2-HG uptake by vascular endothelial cells.
Fig. 3: SLC1A1 deficiency impedes R-2-HG-promoted tumor angiogenesis.
Fig. 4: Restrained R-2-HG uptake activates mitochondrial respiration in vascular endothelial cells.
Fig. 5: R-2-HG influx promotes mitochondrial Na+/Ca2+ exchange in vascular endothelial cells.
Fig. 6: R-2-HG remodels cytoskeleton rearrangement and promotes mitochondrial migration.
Fig. 7: mIDH inhibition suppresses tumor angiogenesis in IDH1-mutant tumors.
Fig. 8: Anticancer activity of mIDH1 inhibitors in IDH1-mutant cholangiocarcinoma.

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Acknowledgements

We thank Prof. Xin Pan (National Center of Biomedical Analysis, Beijing, China) for kindly providing the 4mt-GCaMP6 and 4mt-ATeam1.03 plasmids and for the valuable advice for the study. We thank Prof. Guangwei Du (McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, USA) for providing the Mito-2Strep plasmid, Prof. Qiang Gao (Zhongshan Hospital, Fudan University, Shanghai, China) for gifting the primary cholangiocarcinoma cells, Prof. Lei Chen (Second Military Medical University, Shanghai, China) for gifting LICCF cholangiocarcinoma cell line and Prof. Lili Ji (Shanghai University of Traditional Chinese Medicine, Shanghai, China) for gifting primary HRECs. This work was supported by the National Natural Science Foundation of China (81821005, 91957126, 81903640, 91957120), and the Program of Shanghai Academic Research Leader (20XD1424800).

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M.H. conceived the project and supervised the study; Z.C. initiated the project and discovered R-2-HG-promoted endothelial cell migration and mitochondrial activation; N.A. contributed to the early stage of SLC1A1 discovery; X.W. and J.X. established the role of SLC1A1 in R-2-HG uptake, discovered SLC1A1-dependent mitochondrial Na+/Ca2+ exchange, and demonstrated the role of SLC1A1 in R-2-HG-promoted angiogenesis in vivo; S.T. characterized mIDH1 inhibitors; L.J. invented HH2301; Y.Zhang and L.L. supervised the preclinical development of HH2301 and verified HH2301 compound-related information; T.W., S.Cao., Y.Liu., A.B., Yuehong.C., X.G., Y.D. and Y.Zheng. performed part of experiments; Y.F., Y.Li., L.Y. and L.T. provided technique assistance; Qingli.Z., X.L. and J.L. conducted R-2-HG measurement; S.Chen, S.G., K.M., M.W. and C.L. purified IDH1 proteins and performed MST assay; S.-H.L. performed metabolome analysis; S.Z. and Qiansen.Z. did SLC1A1 molecular modeling and docking; Y.S. and Yi.C. performed part of PDX studies; L.Z. and M.T. performed proteomics analysis; X.W. and J.X. prepared all figures; M.H., X.W. and J.X. wrote the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Min Huang.

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Competing interests

L.J. was a full-time employee of Haihe Biopharma Co, Ltd..Y.Zhang and L.L. are full-time employees of Haihe Biopharma Co, Ltd.. Haihe Biopharma has filed a patent for HH2301 and L.J., M.H., S.T. and X.L. are co-inventors. M.H. is a paid consultant of Haihe Biopharma.

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Wang, X., Chen, Z., Xu, J. et al. SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors. Cell Res 32, 638–658 (2022). https://doi.org/10.1038/s41422-022-00650-w

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