MYC Drives Group 3 Medulloblastoma through Transformation of Sox2+ Astrocyte Progenitor Cells.
MYC Drives Group 3 Medulloblastoma through Transformation of Sox2+ Astrocyte Progenitor Cells.
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DOI：
10.1158/0008-5472.can-18-1787
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发表时间：
2019-03
期刊：
影响因子：
11.2
通讯作者：
Ran Tao;Najiba Murad;Zhenhua Xu;Peng Zhang;K. Okonechnikov;M. Kool;S. Rivero-Hinojosa;C. Lazarski;P. Zheng;Yang Liu;C. Eberhart;Brian R. Rood;R. Packer;Yanxin Pei
中科院分区：
文献类型：
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作者：
Ran Tao;Najiba Murad;Zhenhua Xu;Peng Zhang;K. Okonechnikov;M. Kool;S. Rivero-Hinojosa;C. Lazarski;P. Zheng;Yang Liu;C. Eberhart;Brian R. Rood;R. Packer;Yanxin Pei
第三组髓母细胞瘤的一个亚组经常存在MYC的扩增或过度表达，但缺乏额外的局灶性异常，但尚不清楚MYC过度表达是否单独可以诱导肿瘤的发生，以及哪些细胞导致了这些肿瘤。在这里，我们表明，出生后早期小脑的星形胶质细胞前体细胞对MYC的转化易感。根据组织学和基因表达谱，由此产生的肿瘤与人类第3组髓母细胞瘤特别相似。MYC驱动的髓母细胞瘤细胞的基因表达分析显示，葡萄糖代谢途径发生改变，乳酸脱氢酶A(LDHA)明显过表达。在人类第3组髓母细胞瘤中，LDHA丰度与MYC表达呈正相关，且与预后不良相关。抑制LDHA可显著抑制小鼠和人MYC驱动的肿瘤的生长，但对正常小脑细胞或SHH相关的髓母细胞瘤几乎没有影响。通过建立一个新的小鼠模型，我们首次证明了星形胶质细胞前体细胞可以被MYC转化，并作为第3组髓母细胞瘤的起源细胞。此外，我们确定LDHA是治疗这种毁灭性疾病的新的、特异的治疗靶点。意义：一个新模型的发现将LDHA确定为第三组髓母细胞瘤的新靶点，为开发有效的治疗该疾病铺平了道路。
A subset of group 3 medulloblastoma frequently harbors amplification or overexpression of MYC lacking additional focal aberrations, yet it remains unclear whether MYC overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by MYC. The resulting tumors specifically resembled human group 3 medulloblastoma based on histology and gene-expression profiling. Gene-expression analysis of MYC-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (LDHA). LDHA abundance correlated positively with MYC expression and was associated with poor prognosis in human group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human MYC-driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma. By generating a new mouse model, we demonstrated for the first time that astrocyte progenitors can be transformed by MYC and serve as the cells of origin for group 3 medulloblastoma. Moreover, we identified LDHA as a novel, specific therapeutic target for this devastating disease. SIGNIFICANCE: Insights from a new model identified LDHA as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.