Cancer Cell：MYCN的时空性转录差异决定脑瘤类型

5月14日，国际肿瘤学著名杂志Cancer Cell发表了加州大学旧金山分校William A. Weiss领导的研究小组的研究论文“Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC”。首次阐明时空性转录差异导致神经干细胞对癌基因MYCN信号不同的反应可引发不同类型的脑瘤。

以往研究表明在许多类型的人类脑瘤中原癌基因MYCN都呈现异常的表达。为了阐明MYCN基因的发育和区域性表达差异对于正常神经细胞向癌细胞转化的影响，William A. Weiss研究组将野生型和突变型（N-mycT58A）小鼠N-myc基因转入来源于围产期小鼠小脑、脑干及前脑的神经干细胞（NSCs）。

结果发现，转入了野生型N-myc神经干细胞不能通过移植形成肿瘤。转入了突变型（N-mycT58A）小鼠N-myc基因的小脑和脑干NSCs形成成神经管细胞瘤和原始神经外胚层瘤，而N-mycT58A前脑NSCs则形成扩散性胶质细胞瘤。

分析表明上述来源于不同区域的肿瘤表达谱是不同的。胚胎期小脑NSCs的肿瘤表现为Sonic Hedgehog (SHH) 依赖性，而来源于出生后小鼠小脑NSCs的肿瘤表现为SHH非依赖性。这种差异部分受到转录因子SOX9的调节。该因子在人成神经管细胞瘤SHH亚型中呈激活状态。该研究证明对于同一原癌基因激活信号，NSCs可以因为发育阶段和区域位置的不同而做出不同的反应，发生不同的转化。

doi:10.1016/j.cell.2011.10.017
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Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC

Fredrik J. Swartling1, 2, ,  , Vasil Savov2, 5, Anders I. Persson1, 5, Justin Chen1, Christopher S. Hackett1, Paul A. Northcott3, Matthew R. Grimmer1, Jasmine Lau1, Louis Chesler4, Arie Perry1, Joanna J. Phillips1, Michael D. Taylor3 and William A. Weiss

The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-mycWT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.