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

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

doi:10.1038/s41422-022-00650-w

Cited by 35 publications

(17 citation statements)

References 65 publications

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“…Recent studies have revealed that EAAT2 is upregulated in at least three types of tumors (gastric, colorectal and breast cancers) [37][38][39][40] , and other cancers might utilize EAAT2 and/or other EAATs for their aggressive phenotypes including, but not limited to, malignant progression and resistance to chemoand endocrine therapies. Consistently, research published in 2022 reported that EAAT3 enhances tumor angiogenesis 61 . Therefore, although further experiments to reveal the BBB impermeability and anti-cancer effects are required, WAY213613 and its derivative compounds may pave the way for future research and/or strategies for cancer therapies.…”

Section: Characterization Of Molecular Features Of Eaat2supporting

confidence: 62%

Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2

et al. 2022

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Glutamate is a pivotal excitatory neurotransmitter in mammalian brains, but excessive glutamate causes numerous neural disorders. Almost all extracellular glutamate is retrieved by the glial transporter, Excitatory Amino Acid Transporter 2 (EAAT2), belonging to the SLC1A family. However, in some cancers, EAAT2 expression is enhanced and causes resistance to therapies by metabolic disturbance. Despite its crucial roles, the detailed structural information about EAAT2 has not been available. Here, we report cryo-EM structures of human EAAT2 in substrate-free and selective inhibitor WAY213613-bound states at 3.2 Å and 2.8 Å, respectively. EAAT2 forms a trimer, with each protomer consisting of transport and scaffold domains. Along with a glutamate-binding site, the transport domain possesses a cavity that could be disrupted during the transport cycle. WAY213613 occupies both the glutamate-binding site and cavity of EAAT2 to interfere with its alternating access, where the sensitivity is defined by the inner environment of the cavity. We provide the characterization of the molecular features of EAAT2 and its selective inhibition mechanism that may facilitate structure-based drug design for EAAT2.

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Section: Characterization Of Molecular Features Of Eaat2supporting

confidence: 62%

Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2

et al. 2022

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“…In glioma and neuroblastoma, downregulation of EAAT1 and EAAT2 and associated reduction in glutamate uptake has been linked to tumor progression and invasion ( 43 , 44 , 45 ). In peripheral tumor types such as breast and gastric cancers, upregulation of EAAT1 and EAAT2 can support tumor metabolism and promote resistance to therapy and other stressors ( 46 , 47 , 48 , 49 , 50 ). In experimental cell models of such peripheral malignancies, modulation of EAAT activity by GPNA may contribute to the observed anticancer effects of this compound.…”

Section: Discussionmentioning

confidence: 99%

Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family

Freidman¹,

Briot²,

Ryan

2022

Journal of Biological Chemistry

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“…Recent in-vitro studies provided evidence for the uptake of D-2HG by cells typically residing in the TME, via the sodium-dependent dicarboxylate transporter 3 (SLC13A3) [ 35 ] or the glutamate transporter SLC1A1 [ 48 ▪ ] (Fig. 4 ).…”

Section: Cell-extrinsic Roles Of D-2hgmentioning

confidence: 99%

“…Treatments with D-2HG used at nontoxic albeit high concentrations (>5 mmol/l) reduce IL-12 secretion and preclude LPS-induced glycolysis in dendritic cells [ 51 ], and prevent LPS-induced activation in murine microglia by affecting the AMPK/mTOR/NF-κB-signaling pathway [ 52 ]. In endothelial cells, D-2HG fuels mitochondrial respiration and angiogenesis [ 48 ▪ ].…”

Section: Cell-extrinsic Roles Of D-2hgmentioning

confidence: 99%

New insights into the Immune TME of adult-type diffuse gliomas

Richard

Laurenge

Mallat

et al. 2022

Current Opinion in Neurology

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Purpose of reviewAdult-type diffuse gliomas are highly heterogeneous tumors. Bulk transcriptome analyses suggested that the composition of the tumor microenvironment (TME) corresponds to genetic and clinical features. In this review, we highlight novel findings on the intratumoral heterogeneity of IDH-wildtype and IDH-mutant gliomas characterized at single-cell resolution, and emphasize the mechanisms shaping the immune TME and therapeutic implications.Recent findingsEmergent evidence indicates that in addition to genetic drivers, epigenetic mechanisms and microenvironmental factors influence the glioma subtypes. Interactions between glioma and immune cells contribute to immune evasion, particularly in aggressive tumors. Spatial and temporal heterogeneity of malignant and immune cell subpopulations is high in recurrent gliomas. IDH-wildtype and IDH-mutant tumors display distinctive changes in their myeloid and lymphoid compartments, and D-2HG produced by IDH-mutant cells impacts the immune TME.SummaryThe comprehensive dissection of the intratumoral ecosystem of human gliomas using single-cell and spatial transcriptomic approaches advances our understanding of the mechanisms underlying the immunosuppressed state of the TME, supports the prognostic value of tumor-associated macrophages and microglial cells, and sheds light on novel therapeutic options.

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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

Cited by 35 publications

References 65 publications

Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2

Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2

Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family

New insights into the Immune TME of adult-type diffuse gliomas

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