Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways.
Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways.
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DOI：
10.15252/emmm.201707729
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发表时间：
2017-12
影响因子：
11.1
通讯作者：
Niclou SP
中科院分区：
文献类型：
--
作者：
Fack F;Tardito S;Hochart G;Oudin A;Zheng L;Fritah S;Golebiewska A;Nazarov PV;Bernard A;Hau AC;Keunen O;Leenders W;Lund-Johansen M;Stauber J;Gottlieb E;Bjerkvig R;Niclou SP
NADP依赖性异柠檬酸脱氢酶（IDH）的杂合突变定义了绝大多数弥漫性胶质瘤，并与DNA和染色质的高甲基化相关。这些突变引起的代谢失调，无论是否依赖于肿瘤代谢物D‐2‐羟戊二酸（D2HG），目前还不太清楚。在这里，我们应用质谱成像对IDH突变型和IDH野生型胶质瘤的颅内异种移植物进行了高解剖分辨率的原位代谢物分布。该方法还辅以标记营养素的体内示踪，然后进行液相色谱-质谱（LC - MS）分析。选定的代谢物在临床标本上进行验证。我们的数据表明，携带IDH1突变的胶质瘤的磷脂组成存在显著差异。此外，我们发现这些肿瘤的特征是葡萄糖转换减少和能量潜力降低，这与它们的侵袭性降低有关。尽管存在这些差异，我们的数据还表明，D2HG的过量生产不会导致中心碳代谢的全球畸变，这表明了强大的适应机制。有趣的是，D2HG在IDH突变肿瘤中没有显示出定量上重要的葡萄糖来源标记，这表明这种肿瘤代谢物的合成可能依赖于替代碳源。尽管NADPH降低，谷胱甘肽水平保持不变。研究人员发现，编码谷胱甘肽合成关键酶的基因在IDH突变型胶质瘤中高度表达，而半胱甘氨酸β合成酶（CBS）的表达与少突胶质亚型患者的生存率相关。这项研究为IDH1突变胶质瘤的体内代谢提供了详细的和临床相关的见解，并指出了这些肿瘤中新的代谢脆弱性。
Heterozygous mutations in NADP‐dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D‐2‐hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient‐derived xenografts of IDH‐mutant versus IDH wild‐type glioma to profile the distribution of metabolites at high anatomical resolution in situ. This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography–mass spectrometry (LC‐MS) analysis. Selected metabolites were verified on clinical specimen. Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation. Moreover, we show that these tumors are characterized by reduced glucose turnover and a lower energy potential, correlating with their reduced aggressivity. Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand. Intriguingly, D2HG shows no quantitatively important glucose‐derived label in IDH‐mutant tumors, which suggests that the synthesis of this oncometabolite may rely on alternative carbon sources. Despite a reduction in NADPH, glutathione levels are maintained. We found that genes coding for key enzymes in de novo glutathione synthesis are highly expressed in IDH‐mutant gliomas and the expression of cystathionine‐β‐synthase (CBS) correlates with patient survival in the oligodendroglial subtype. This study provides a detailed and clinically relevant insight into the in vivo metabolism of IDH1‐mutant gliomas and points to novel metabolic vulnerabilities in these tumors.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
12.7
作者：
Hartmann, Christian;Meyer, Jochen;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
29
作者：
Marin-Valencia I;Yang C;Mashimo T;Cho S;Baek H;Yang XL;Rajagopalan KN;Maddie M;Vemireddy V;Zhao Z;Cai L;Good L;Tu BP;Hatanpaa KJ;Mickey BE;Matés JM;Pascual JM;Maher EA;Malloy CR;Deberardinis RJ;Bachoo RM
通讯作者：
Bachoo RM
影响因子：
2.6
作者：
Emadi, Ashkan;Ju, Sung Ah;Dang, Chi V.
通讯作者：
Dang, Chi V.