p52 induces mesenchymal differentiation in glioblastoma

项目总结/摘要 该项目的目标是研究p52的作用，p52是五种核因子-kB（NF-kB）亚单位之一， 调节胶质母细胞瘤（GBM）中的间充质（MES）转化。GBM是最常见的原发性胶质细胞 成人肿瘤，尽管积极的多模式治疗，几乎普遍是致命的。的分类 基于基因表达谱将GBM分为分子亚型揭示了几种调控途径 对GBM发病机制至关重要。最近，NF-kB被确定为高度侵袭性的细胞因子的主要调节因子。 MES GBM亚型。我们工作的中心假设是p52诱导GBM中的MES转化， 这种p52特异性通路的调节改变了肿瘤微环境（TME）， 抗GBM治疗我们的目的是检查p52指导亚型的机制的顺序方面。 分化，以发现新的策略，以改善这种毁灭性疾病的治疗。目标1： 检查p52调节对亚型转化的影响。MES的另一个已知的主调节器 在p52的形成中，Stat 3起着关键的作用。我们将检验这样一个假设， Stat 3介导的MES分化通过调节p52的产生而发生。此外，由于NF-kB是一种 调节基因表达的转录因子，我们将研究受 通过全基因组靶点鉴定进行差异p52启动子结合，以阐明关键的潜在靶点 到MES转型。由于亚型之间的转化不仅依赖于细胞内在信号传导， 在目标2中，我们将研究调节p52对细胞外性变化的影响， TME和GBM治疗效果。具体地说，我们将改变免疫活性鼠中p52的表达， GBM模型并检验p52调节改变TME并影响对佐剂的反应的假设 疗法这些互补的目标将定义p52在GBM中MES转化中的作用。从更广泛的 本课题的研究结果将进一步加深我们对GBM分子亚类的认识 转化，并可能导致鉴定新的靶点，可以增强抗GBM治疗， 提高患者生存率。

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.