STAT3 Regulation of Glioblastoma Pathogenesis

描述（由申请人提供）：该提案的长期目标是阐明驱动胶质母细胞瘤发病机制的分子机制，胶质母细胞瘤是最常见和侵袭性的原发性脑肿瘤。我们正采取一种新的神经发育角度来研究胶质母细胞瘤的发病机制。胶质母细胞瘤被认为是由星形胶质细胞或其前体细胞神经干细胞转化而来。在大脑发育过程中，转录因子STAT3在调节神经干细胞的命运规范，包括向星形胶质细胞的分化中起着关键作用。该项目的中心假设是STAT3信号的失调有助于胶质母细胞瘤的发病。使用严格的小鼠遗传学方法，我们发现STAT3在星形胶质细胞中发挥相反的致癌和肿瘤抑制作用，这取决于肿瘤的突变谱。肿瘤抑制因子PTEN缺乏和致癌蛋白EGFRvIII表达的主要遗传改变可能标志着不同类型的胶质母细胞瘤肿瘤。值得注意的是，我们发现STAT3抑制PTEN缺失下游的细胞转化，而STAT3在星形胶质细胞中以EGFRvIII下游的致癌方式表现。我们还发现STAT3抑制pten缺陷胶质母细胞瘤细胞中IL8的转录，从而抑制其增殖和侵袭性。我们的发现提出了STAT3在胶质恶性肿瘤中的作用和机制的基本问题。STAT3介导EGFRvIII诱导星形细胞转化的机制是什么？STAT3如何抑制pten缺陷胶质母细胞瘤细胞中IL8的转录？STAT3信号在人类胶质母细胞瘤癌症干细胞生物学中的作用是什么？我们建议通过实现以下三个具体目标来解决这些问题，(1)通过鉴定STAT3在这种病理反应中下游操作的基因，确定STAT3介导egfrviii诱导的星形细胞转化的机制，(2)鉴定胶质母细胞瘤细胞中将STAT3信号与il - 8抑制结合的转录调节因子，(3)体外和体内确定STAT3在胶质母细胞瘤癌干细胞恶性潜能中的作用。提出的实验代表了一组重要的实验，将显著提高我们对控制胶质母细胞瘤发病机制的转录机制的理解。提出的研究也应该为潜在的确定针对胶质母细胞瘤患者的新治疗策略奠定基础。

DESCRIPTION (provided by applicant): The long-term objectives of the proposal are to elucidate the molecular mechanisms that drive the pathogenesis of glioblastoma, the most common and aggressive primary brain tumor. We are taking a novel neurodevelopmental perspective to the study of glioblastoma pathogenesis. Glioblastoma tumors are thought to arise from the transformation of astrocytes or their precursor cells, the neural stem cells. During brain development, the transcription factor STAT3 plays a critical role in the regulation of neural stem cell fate specification including their differentiation into astrocytes. The central hypothesis of the project is that deregulation of STAT3 signaling contributes to glioblastoma pathogenesis. Using a rigorous mouse genetics approach, we have discovered that STAT3 plays opposing oncogenic and tumor suppressive roles in astrocytes depending on the mutational profile of the tumor. The major genetic alterations of deficiency of the tumor suppressor PTEN and expression of the oncogenic protein EGFRvIII may mark distinct sets of glioblastoma tumors. Remarkably, we have found that STAT3 suppresses cell transformation downstream of PTEN deficiency, whereas STAT3 behaves in an oncogenic manner downstream of EGFRvIII in astrocytes. We have also found that STAT3 represses IL8 transcription in PTEN-deficient glioblastoma cells and thereby inhibits their proliferation and invasiveness. Our findings raise fundamental questions on STAT3's role and mechanisms in glial malignancy. What is the mechanism by which STAT3 mediates the ability of EGFRvIII to induce astrocyte transformation? How does STAT3 repress IL8 transcription in PTEN-deficient glioblastoma cells? What is the role of STAT3 signaling in the biology of human glioblastoma cancer stem cells? We propose to address these questions by achieving the following three specific aims, (1) determine the mechanism by which STAT3 mediates EGFRvIII-induced astrocyte transformation by identifying the genes that operate downstream of STAT3 in this pathobiological response, (2) identify the transcriptional regulators that couple the STAT3 signal to IL8 repression in glioblastoma cells, and (3) determine the function of STAT3 in the malignant potential of glioblastoma cancer stem cells in vitro and in vivo. The proposed experiments represent an important set of experiments that will significantly improve our understanding of the transcriptional mechanisms that govern glioblastoma pathogenesis. The proposed studies should also lay the foundation for potential identification of novel therapeutic strategies in patient-tailored treatment of glioblastoma. PUBLIC HEALTH RELEVANCE: Glioblastoma is the most common and deadly tumor that has its origins in the brain. A major obstacle in developing effective treatments for glioblastoma is our poor understanding of the biology of this tumor. In my laboratory, we are asking if abnormalities of biochemical mechanisms that control the normal development of specific brain cells could explain how these tumors arise. Addressing these questions will help us gain a deep mechanistic understanding of how glioblastoma tumors arise and should lay the foundation for potential development of personalized therapy in the future for patients diagnosed with this deadly tumor.