Mechanisms of glioblastoma multiforme invasion: the role of STAT3

描述(申请人提供)：在最常见的成人原发脑瘤中，多形性胶质母细胞瘤(GBM)是恶性程度最高的。尽管在手术、化疗和放射治疗方面取得了进展，但基底膜仍然是一种毁灭性的疾病。基底膜的一个特点是能够渗入白质束，但人们对获得弥漫性特征的分子机制知之甚少。PTEN编码磷脂酰肌醇-3激酶途径的负调控因子，在基底膜中常见突变，并参与调节肿瘤的迁移。这一提议的基本假设是，决定正常神经胶质发育的过程中的异常有助于恶性转化。以往的研究已经证实，转录因子STAT3的激活在神经干细胞向星形胶质细胞分化过程中起着关键作用。在初步数据中，STAT3缺失增加了体外培养的小鼠星形胶质细胞的迁移。此外，在人类GBM样本中，低PTEN表达与低STAT3活性相关。综上所述，这些结果提出了一种有趣的可能性，即STAT3抑制PTEN缺失的基底膜的侵袭性。本研究的具体目的是：1)在脑片和活体实验中测试STAT3在GBM侵袭性中的作用；2)利用表达阵列分析鉴定控制GBM迁移的STAT3反应基因；3)通过基于RNA干扰的筛选，确定调控GBM侵袭性的新的细胞内在机制。这些目标将使用分子生物学、细胞培养、脑片制备和体内方法相结合来实现。这些目标的完成将阐明STAT3在基底膜侵袭性中的作用，并可能揭示治疗基底膜的新靶点。

DESCRIPTION (provided by applicant): Among gliomas, the most common primary brain tumor in adults, glioblastoma multiforme (GBM) is the most malignant. Despite advances in surgery, chemotherapy, and radiation, GBM remains a devastating disease. A hallmark of GBM is ts ability to infiltrate white matter tracts, but little is known about the molecular mechanisms underlying the acquisition of nvasive characteristics. PTEN, which encodes a negative regulator of the phosphoinositide-3 kinase pathway, is commonly mutated in GBMs and has been implicated in regulation of tumor migration. The underlying hypothesis of this proposal is that abnormalities in processes that determine normal glial development contribute to malignant transformation. Previous studies have identified a critical role for activation of STAT3, a transcription factor, in the differentiation of neural stem cells into astrocytes. In preliminary data, STAT3 loss increased the migration of murine astrocytes in vitro. Moreover, in human GBM samples, low PTEN expression correlated with low STAT3 activity. Together, these results raise the intriguing possibility that STAT3 inhibits invasiveness in PTEN-deficient GBMs. The specific aims of this study are: 1) to test the role of STAT3 in GBM invasiveness in brain slice assay and in vivo, 2) to dentify STAT3-responsive genes that control GBM migration using expression array analysis, and 3) to identify novel cell-intrinsic mechanisms that regulate GBM invasiveness through an RNA interference-based screen. These aims will be pursued using a combination of molecular biology, cell culture, brain slice preparation, and in vivo approaches. Completion of these aims will elucidate the role of STAT3 in GBM invasiveness and potentially reveal new therapeutic argets against GBM.