Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress
Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress
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DOI：
10.1096/fj.201800907rr
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发表时间：
2019-01-01
期刊：
影响因子：
4.8
通讯作者：
Leenders, William P. J.
中科院分区：
文献类型：
--
作者：
Lenting, Krissie;Khurshed, Mohammed;Leenders, William P. J.
弥漫性神经胶质瘤通常携带异柠檬酸脱氢酶 (IDH1(mut)) 点突变，导致代谢应激。尽管 IDHmut 神经胶质瘤很难在体外培养，但它们通过弥漫性浸润在大脑中茁壮成长，这表明大脑特异性的肿瘤-基质相互作用可以补偿 IDH-1 缺陷。为了阐明临床 IDHmut 神经胶质瘤中导致其恶性的代谢调整，我们将最近开发的靶向定量 RNA 下一代测序方法应用于 66 个临床神经胶质瘤和相关的原位神经胶质瘤异种移植物，无论是否有内源性 IDH-1(R132H) 突变。使用曼哈顿图计算表达谱之间的距离，使用 Ward 方法执行无监督凝聚聚类，以及使用 Mann Whitney U 检验和 Fisher 精确检验进行监督组分析，在 R 中分析数据集。通过蛋白质分析、原位酶活性图谱和原位 IDH1(mut)-和 IDHwt-神经胶质瘤异种移植物的体内磁共振波谱研究转录组数据的重要性。临床 IDH1(mut) 神经胶质瘤的基因集富集分析强烈表明乳酸和神经递质谷氨酸的分解代谢的作用，而在 IDHwt 神经胶质瘤中，葡萄糖和谷氨酰胺的加工是主要的代谢途径。这些癌症中差异代谢活性的进一步证据来自原位酶图谱研究和临床前体内磁共振波谱成像。我们的数据支持一种进化模型，其中 IDHmut 神经胶质瘤细胞与支持性神经元细胞和星形胶质细胞作为谷氨酸和乳酸的供应者共生，这可能解释了这些癌症的弥散性。对谷氨酸和乳酸的依赖为治疗 IDHmut 神经胶质瘤的新方法开辟了道路。Lenting, K.、Khurshed, M.、Peeters, T. H.、van den Heuvel, C. N. A. M.、van Lith, S. A. M.、de Bitter, T.、Hendriks, W.、Span, P. N.、Molenaar, R. J.、Botman, D., Verrijp, K., Heerschap, A., ter Laan, M., Kusters, B., van Ewijk, A., Huynen, M. A., van Noorden, C. J. F., Leenders, W. P. J. 异柠檬酸脱氢酶 1 突变的人类神经胶质瘤依赖于乳酸和谷氨酸来缓解代谢应激。
Diffuse gliomas often carry point mutations in isocitrate dehydrogenase (IDH1(mut)), resulting in metabolic stress. Although IDHmut gliomas are difficult to culture in vitro, they thrive in the brain via diffuse infiltration, suggesting brain-specific tumor-stroma interactions that can compensate for IDH-1 deficits. To elucidate the metabolic adjustments in clinical IDHmut gliomas that contribute to their malignancy, we applied a recently developed method of targeted quantitative RNA next-generation sequencing to 66 clinical gliomas and relevant orthotopic glioma xenografts, with and without the endogenous IDH-1(R132H) mutation. Datasets were analyzed in R using Manhattan plots to calculate distance between expression profiles, Ward's method to perform unsupervised agglomerative clustering, and the Mann Whitney U test and Fisher's exact tests for supervised group analyses. The significance of transcriptome data was investigated by protein analysis, in situ enzymatic activity mapping, and in vivo magnetic resonance spectroscopy of orthotopic IDH1(mut)- and IDHwt-glioma xenografts. Gene set enrichment analyses of clinical IDH1(mut) gliomas strongly suggest a role for catabolism of lactate and the neurotransmitter glutamate, whereas, in IDHwt gliomas, processing of glucose and glutamine are the predominant metabolic pathways. Further evidence of the differential metabolic activity in these cancers comes from in situ enzymatic mapping studies and preclinical in vivo magnetic resonance spectroscopy imaging. Our data support an evolutionary model in which IDHmut glioma cells exist in symbiosis with supportive neuronal cells and astrocytes as suppliers of glutamate and lactate, possibly explaining the diffuse nature of these cancers. The dependency on glutamate and lactate opens the way for novel approaches in the treatment of IDHmut gliomas.Lenting, K., Khurshed, M., Peeters, T. H., van den Heuvel, C. N. A. M., van Lith, S. A. M., de Bitter, T., Hendriks, W., Span, P. N., Molenaar, R. J., Botman, D., Verrijp, K., Heerschap, A., ter Laan, M., Kusters, B., van Ewijk, A., Huynen, M. A., van Noorden, C. J. F., Leenders, W. P. J. Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress.