Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3
Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3
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DOI：
10.1073/pnas.1221478110
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发表时间：
2013-05-21
影响因子：
11.1
通讯作者：
Nakano, Ichiro
中科院分区：
文献类型：
--
作者：
Mao, Ping;Joshi, Kaushal;Nakano, Ichiro
高级别胶质瘤（HGG）的肿瘤异质性被基于核心基因特征的四种临床相关亚型所识别。然而，胶质瘤干细胞（GSC）在个别HGG亚型的分子信号转导的特点很差。在这里，我们确定和特点的两个相互排斥的GSC亚型与不同的失调信号通路。mRNA谱分析区分前神经（PN）间充质（Mes）GSC，并揭示了与相应的PN或Mes HGG的显着相关性。Mes GSC在体外和小鼠颅内异种移植物中显示出更具侵袭性的表型。此外，与PN GSC相比，Mes GSC对辐射具有显著抗性。糖酵解途径，包括醛脱氢酶（ALDH）家族基因，特别是ALDH1A3，在Mes GSC中富集。糖酵解活性和ALDH活性在Mes GSC中显著升高，但在PN GSC中不显著。ALDH1A3在临床HGG中的表达也高于低级别胶质瘤或正常脑组织。此外，ALDH1A3的抑制减弱了Mes而不是PN GSC的生长。最后，PN GSC的辐射处理上调Mes相关标记物和下调PN相关标记物，而ALDH1A3的抑制减弱了PN GSC中Mes身份的辐射诱导增益。总之，我们的数据表明，GSC的两种亚型，窝藏不同的代谢信号传导途径，代表肿瘤间胶质瘤异质性，并强调ALDH1A3相关的信号传导，促进异常增殖的Mes HGG和GSC以前未确定的作用。因此，抑制ALDH1A3介导的通路可能为具有Mes特征的HGG亚组提供有希望的治疗方法。
Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent inter-tumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.