Wnt/Planar Cell Polarity Contribution to Glioblastoma Multiforme Invasion and Therapeutic Resistance

项目摘要 多形性胶质母细胞瘤（GBM）是恶性脑癌的最常见形式，并且具有高度侵袭性， GBM细胞的高度浸润性降低了GBM的临床疗效。 虽然已经探索了更有效的患者定制疗法的前景，但这些策略 迄今为止都失败了，因为肿瘤总是高度耐药的。Wnt/Planar Cell Polarity（PCP）是一种非线性的 典型的Wnt信号通路，促进全局方向线索产生局部极化的细胞行为， 导致细胞运动性、存活和增殖增加。Wnt/PCP对胚胎发育至关重要 过程，在那里它调节细胞粘附和迁移。Wnt/PCP信号在肿瘤中的新作用 恶性肿瘤巩固了肿瘤重新激活发育程序以促进其 攻击性行为Wnt/PCP通路组分的表达模式强烈提示GBM肿瘤 参与促进侵入性和治疗抗性的途径，强调更深层次的 对GBM中Wnt/PCP的理解可以发现新的治疗方法。驱动这一假设的是 提出的研究是，Wnt/PCP信号直接有助于GBM的恶性性质，包括 增殖、运动性、侵袭性和治疗抗性。具体目标1将严格描述 Wnt/PCP信号转导通过细胞、分子和生物学机制驱动GBM的恶性特性， 生物化学技术，重点是Wnt5a/Fzd7配体/受体对的参与。具体目标2将 采用敲低和外源表达方法，以确定PCP成分 导致GBM对靶向治疗剂的抗性。将检查体外结果和体内结果的总结 在Specific Aim 3中使用原位和患者来源的GBM异种移植小鼠模型。成功 该项目的完成将巩固Wnt/PCP通路在GBM恶性肿瘤中的参与，并揭示 新的治疗干预的目标到疾病。

Project Summary Glioblastoma multiforme (GBM) is the most common form of malignant brain cancer, and is highly aggressive, recurrent, and difficult to treat. The highly infiltrative nature of GBM cells diminishes the clinical efficacy of surgery, and while the prospect of more effective patient-tailored therapies has been explored, such strategies have thus far failed because tumors are invariably highly resistant. Wnt/Planar Cell Polarity (PCP) is a non- canonical Wnt signaling pathway that promotes global directional cues to produce locally polarized cell behavior, leading to increased cell motility, survival and proliferation. Wnt/PCP is critical for embryonic developmental processes, where it modulates cell adhesion and migration. The emerging role for Wnt/PCP signaling in tumor malignancy solidifies the recurring theme that tumors reactivate developmental programs to promote their aggressive behaviors. Expression patterns of Wnt/PCP pathway components strongly suggest that GBM tumors engage the pathway to promote invasiveness and therapeutic resistance, underscoring the notion that a deeper understanding of Wnt/PCP in GBM could uncover novel therapeutic approaches. The hypothesis driving the proposed studies is that Wnt/PCP signaling directly contributes to the malignant properties of GBM, including proliferation, motility, invasiveness and therapeutic resistance. Specific Aim 1 will rigorously characterize the mechanisms by which Wnt/PCP signaling drives the malignant properties of GBM using cellular, molecular and biochemical techniques, focusing on the involvement of the Wnt5a/Fzd7 ligand/receptor pair. Specific Aim 2 will employ knockdown and exogenous expression methods to determine the extent to which PCP components contribute to GBM resistance to targeted therapeutics. Recapitulation of in vitro findings in vivo will be examined in Specific Aim 3 using orthotopic and patient-derived xenograft mouse models of GBM. The successful completion of the project will solidify the involvement of the Wnt/PCP pathway in GBM malignancy, and reveal novel targets for therapeutic intervention into the disease.