In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors.
In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors.
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DOI：
10.1016/j.cmet.2017.10.001
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发表时间：
2017-12-05
期刊：
影响因子：
29
通讯作者：
Keshari KR
中科院分区：
文献类型：
--
作者：
Salamanca-Cardona L;Shah H;Poot AJ;Correa FM;Di Gialleonardo V;Lui H;Miloushev VZ;Granlund KL;Tee SS;Cross JR;Thompson CB;Keshari KR
肿瘤代谢物2-羟基戊二酸（2-HG）是各种癌症的标志性生物标志物，它是异柠檬酸脱氢酶（IDH）突变的结果。在多种癌症中，2-HG的代谢来源决定了其产生和潜在的治疗策略，但这仍然难以在体内获得。在这里，利用患者来源的软骨肉瘤细胞携带内源性IDH1和2突变，我们报道了2- hg可以在体外由谷氨酰胺快速生成。然后，使用超极化磁共振成像（HP- mri），我们证明体内HP [1-13C]谷氨酰胺可用于无创测量谷氨酰胺衍生的HP 2-HG生成。这可以很容易地利用选择性IDH1抑制剂进行调节，为靶向谷氨酰胺衍生的2-HG治疗打开了大门。体内HP 2-HG的快速生成进一步表明，在一种依赖环境的方式下，谷氨酰胺可能是突变型IDH肿瘤中2-HG产生的主要碳源。Salamanca-Cardona等人的研究表明，谷氨酰胺是突变型IDH肿瘤代谢产物2-羟戊二酸生物合成的主要碳源。他们开发了一种新的超极化MRI方法，使用谷氨酰胺作为探针，实时、无创、高特异性地检测体内2-羟基戊二酸的形成。
The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and 2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1-13C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors. Salamanca-Cardona et al. show that glutamine is a primary carbon-source for the biosynthesis of the oncometabolite 2-hydroxyglutarate in mutant IDH tumors. They develop a novel hyperpolarized MRI method using glutamine as a probe to detect 2-hydroxyglutarate formation in vivo in real-time, non-invasively, and with high specificity.
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影响因子：
64.8
作者：
通讯作者：
--
具有IDH1突变的胶质瘤细胞通过丙酮酸羧化酶调节代谢分数通量。
影响因子：
3.7
作者：
Izquierdo-Garcia JL;Cai LM;Chaumeil MM;Eriksson P;Robinson AE;Pieper RO;Phillips JJ;Ronen SM
通讯作者：
Ronen SM
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
12.7
作者：
Capper, David;Zentgraf, Hanswalter;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
影响因子：
16.6
作者：
Chaumeil, Myriam M.;Larson, Peder E. Z.;Ronen, Sabrina M.
通讯作者：
Ronen, Sabrina M.