p52 induces mesenchymal differentiation in glioblastoma

项目摘要/摘要 这个项目的目标是研究p52，五个核因子-kB(nf-kB)亚基之一，在 调节间充质(MES)在胶质母细胞瘤中的转化。基底膜是最常见的初级神经胶质细胞。 尽管积极的多模式治疗，但几乎所有人都是致命的。第二部分：分类问题 基于基因表达谱的GBM分子亚型揭示了几种调控途径 对GBM的发病起关键作用。最近，核因子-kB被确定为高度侵袭性的主要调节因子。 MES GBM亚型。我们工作的中心假设是p52诱导了GBM的MES转换和 这种p52特异性通路的调节改变了肿瘤微环境(TME)，影响了疗效 抗基底膜治疗。我们的目的是研究p52引导亚型的机制的顺序方面。 以发现新的策略来改进这种毁灭性疾病的治疗。在目标1中，我们 研究p52调控对亚型转化的影响。另一个已知的MES主调节器 分化，即STAT3，在促进p52的形成中起着关键作用。我们将检验这一假设 STAT3介导的MES分化是通过调节p52的产生来实现的。此外，由于核因子-kB是一种 调控基因表达的转录因子，我们将研究其影响的下游图谱 通过全基因组靶点鉴定差异p52启动子结合来阐明潜在的关键靶点 向MES转型。AS亚型之间的转换不仅取决于细胞内的信号转导 途径，但也对细胞的外在变化，在目标2，我们将研究调制p52对 TME和对GBM的治疗效果。具体地说，我们将改变具有免疫能力的小鼠的p52表达 GBM建立并检验P52调节改变TME并影响佐剂反应的假说 心理治疗。这些互补的目标将定义p52在GBM的MES转换中的作用。从更广泛的 展望未来，本项目的成果将扩大我们对GBM分子亚类的理解 转化，并可能导致识别新的靶点，可以加强抗GBM治疗和 提高患者存活率。

PROJECT SUMMARY/ABSTRACT The goal of this project is to examine the role of p52, one of the five nuclear factor-kB (NF-kB) subunits, in regulating mesenchymal (MES) transformation in glioblastoma (GBM). GBM is the most common primary glial neoplasm in adults and, despite aggressive multimodal therapy, is nearly universally fatal. The classification of GBM into molecular subtypes based on gene expression profiles has revealed several regulatory pathways critical to GBM pathogenesis. Recently, NF-kB was identified as a master regulator of the highly aggressive MES GBM subtype. The central hypothesis of our work is that p52 induces MES transformation in GBM and that modulation of this p52-specific pathway alters the tumor microenvironment (TME) and affects the efficacy of anti-GBM therapy. Our aims examine sequential aspects of the mechanism by which p52 directs subtype differentiation to uncover novel strategies to improve the treatment of this devastating disease. In Aim 1, we examine the effects of p52 modulation on subtype transformation. Another known master regulator of MES differentiation, Stat3, plays a critical role in promoting p52 formation. We will examine the hypothesis that Stat3-mediated MES differentiation occurs through regulation of p52 production. Additionally, as NF-kB is a transcription factor that modulates gene expression, we will examine the downstream profile affected by differential p52 promoter binding through genome-wide target-identification to elucidate potential targets critical to MES transformation. As transformation between subtypes is dependent not only on cell-intrinsic signaling pathways, but also on cell-extrinsic changes, in Aim 2 we will investigate the impact of modulating p52 on the TME and on GBM treatment efficacy. Specifically, we will alter p52 expression in an immunocompetent murine GBM model and test the hypothesis that p52 modulation alters the TME and affects the response to adjuvant therapy. These complimentary aims will define the role of p52 in MES transformation in GBM. From a broader perspective, the results of the current project will expand our understanding of GBM molecular subclass transformation and potentially lead to the identification of novel targets that can enhance anti-GBM therapy and improve patient survival.