Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target
Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target
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DOI：
10.1073/pnas.0608396103
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发表时间：
2006-11-14
影响因子：
11.1
通讯作者：
Mischel, P. S.
中科院分区：
文献类型：
--
作者：
Horvath, S.;Zhang, B.;Mischel, P. S.
胶质母细胞瘤是成人最常见的原发性恶性脑肿瘤，也是所有癌症中最致命的一种。尽管进行了手术、放疗和化疗，但患有这种疾病的患者从诊断开始的中位生存期为15个月。需要新的治疗方法。最近的研究表明，胶质母细胞瘤患者可能受益于分子靶向治疗。在这里，我们解决了迫切需要确定新的分子靶点。利用来自两组独立的临床肿瘤样本（n = 55和n = 65）的全球基因表达数据，我们确定了胶质母细胞瘤中的基因共表达模块，该模块也存在于乳腺癌中，并与未分化癌症的“元特征”显著重叠。在同基因模型系统中的研究表明，该模块是突变型表皮生长因子受体EGFRvIII的下游，并且它可以被表皮生长因子受体酪氨酸激酶抑制剂厄洛替尼抑制。我们确定ASPM（异常纺锤状小头畸形相关）作为该模块中的关键基因，并证明其在胶质母细胞瘤中相对于正常脑（或身体组织）的过表达。最后，我们表明，ASPM抑制siRNA介导的敲低抑制肿瘤细胞增殖和神经干细胞增殖，支持ASPM作为胶质母细胞瘤的潜在分子靶点。我们的加权基因共表达网络分析为利用基因组数据识别胶质母细胞瘤的关键控制网络和分子靶点提供了蓝图，并且从我们的工作中洗脱的原则可以应用于其他癌症。
Glioblastoma is the most common primary malignant brain tumor of adults and one of the most lethal of all cancers. Patients with this disease have a median survival of 15 months from the time of diagnosis despite surgery, radiation, and chemotherapy. New treatment approaches are needed. Recent works suggest that glioblastoma patients may benefit from molecularly targeted therapies. Here, we address the compelling need for identification of new molecular targets. Leveraging global gene expression data from two independent sets of clinical tumor samples (n = 55 and n = 65), we identify a gene coexpression module in glioblastoma that is also present in breast cancer and significantly overlaps with the "metasignature" for undifferentiated cancer. Studies in an isogenic model system demonstrate that this module is downstream of the mutant epidermal growth factor receptor, EGFRvIII, and that it can be inhibited by the epidermal growth factor receptor tyrosine kinase inhibitor Erlotinib. We identify ASPM (abnormal spindle-like microcephaly associated) as a key gene within this module and demonstrate its overexpression in glioblastoma relative to normal brain (or body tissues). Finally, we show that ASPM inhibition by siRNA-mediated knockdown inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM as a potential molecular target in glioblastoma. Our weighted gene coexpression network analysis provides a blueprint for leveraging genomic data to identify key control networks and molecular targets for glioblastoma, and the principle eluted from our work can be applied to other cancers.