Mechanisms of glioblastoma multiforme invasion: the role of STAT3

描述（申请人提供）：在成人最常见的原发性脑肿瘤胶质瘤中，多形性胶质母细胞瘤（GBM）是最恶性的。尽管手术、化疗和放疗都取得了进展，但GBM仍然是一种毁灭性的疾病。GBM的一个标志是其浸润白质束的能力，但对获得浸润性特征的分子机制知之甚少。PTEN编码磷酸肌醇-3激酶途径的负调节因子，在GBMs中通常发生突变，并与肿瘤迁移的调节有关。这一提议的基本假设是，决定正常胶质发育过程的异常有助于恶性转化。先前的研究已经确定了STAT3（一种转录因子）的激活在神经干细胞向星形胶质细胞的分化过程中起着关键作用。在初步数据中，STAT3缺失增加了小鼠星形胶质细胞在体外的迁移。此外，在人类GBM样本中，低PTEN表达与低STAT3活性相关。总之，这些结果提出了STAT3抑制pten缺陷GBMs侵袭性的有趣可能性。本研究的具体目的是：1)通过脑切片实验和体内实验检测STAT3在GBM侵袭性中的作用；2)通过表达阵列分析鉴定控制GBM迁移的STAT3应答基因；3)通过基于RNA干扰的筛选鉴定调节GBM侵袭性的新的细胞内在机制。这些目标将通过结合分子生物学、细胞培养、脑切片制备和体内方法来实现。这些目标的完成将阐明STAT3在GBM侵袭中的作用，并可能揭示针对GBM的新治疗靶点。

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.