Mechanisms of glioblastoma multiforme invasion: the role of STAT3

描述（由申请人提供）：在胶质瘤（成人最常见的原发性脑肿瘤）中，多形性胶质母细胞瘤（GBM）恶性程度最高。尽管在手术、化疗和放疗方面取得了进展，GBM仍然是一种毁灭性的疾病。GBM的一个标志是其浸润白色物质束的能力，但对获得侵袭性特征的分子机制知之甚少。编码磷酸肌醇-3激酶途径的负调节剂的PTEN通常在GBM中突变，并且已经涉及肿瘤迁移的调节。这一提议的基本假设是，决定正常胶质细胞发育的过程异常有助于恶性转化。先前的研究已经确定了转录因子STAT 3的激活在神经干细胞向星形胶质细胞分化中的关键作用。在初步数据中，STAT 3的丢失增加了体外鼠星形胶质细胞的迁移。此外，在人GBM样品中，低PTEN表达与低STAT 3活性相关。总之，这些结果提出了一种有趣的可能性，即STAT 3抑制PTEN缺陷GBM的侵袭性。本研究的具体目的是：1）在脑切片测定和体内测试STAT 3在GBM侵袭性中的作用，2）使用表达阵列分析鉴定控制GBM迁移的STAT 3应答基因，和3）通过基于RNA干扰的筛选鉴定调节GBM侵袭性的新细胞内在机制。这些目标将采用分子生物学、细胞培养、脑切片制备和体内方法的组合来实现。这些目标的实现将阐明STAT 3在GBM侵袭中的作用，并可能揭示针对GBM的新的治疗靶点。

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.