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

Wnt/平面细胞极性对多形性胶质母细胞瘤侵袭和治疗耐药的贡献

基本信息

批准号：
10320922
负责人：
Courtney Anne Dreyer
金额：
$ 3.89万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320922
关键词：
Actins Aggressive behavior Automobile Driving Biochemical Biological Models Brain Cell Adhesion Cell Line Cell Proliferation Cell Survival Cells Clinical Complex Core Protein Cues Development Developmental Process Disease Elements Embryo Epidermal Growth Factor Receptor Excision Glioblastoma Goals Growth Growth Factor Receptors In Vitro JUN gene Lesion Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Membrane Methods Modeling Molecular Mus Mutation Nature Oncogenes Oncogenic Operative Surgical Procedures Outcome PDGFRB gene PTEN gene Pathway interactions Patients Pattern Penetration Pharmaceutical Preparations Phenotype Phosphotransferases Play Property Protein Tyrosine Kinase Publishing Radiation therapy Recurrence Resistance Role Signal Pathway Signal Transduction Solid Neoplasm Survival Rate Techniques Testing Therapeutic Therapeutic Intervention WNT Signaling Pathway Xenograft procedure arm brain tissue cell behavior cell growth cell motility chemotherapy clinical efficacy diagnostic strategy improved in vitro Model in vivo in vivo Model individualized medicine knock-down metaplastic cell transformation mouse model new therapeutic target novel novel therapeutic intervention patient derived xenograft model planar cell polarity polarized cell programs receptor targeted treatment temozolomide therapeutically effective therapy resistant treatment strategy tumor tumor growth

项目摘要

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.

项目概要多形性胶质母细胞瘤 (GBM) 是最常见的恶性脑癌，具有高度侵袭性，反复发作，治疗难度大。 GBM 细胞的高度浸润性降低了临床疗效手术，虽然已经探索了更有效的针对患者的治疗方法的前景，但此类策略迄今为止，这种方法都失败了，因为肿瘤总是具有高度耐药性。 Wnt/平面电池极性 (PCP) 是一种非典型的 Wnt 信号通路促进全局定向信号产生局部极化的细胞行为，导致细胞运动、存活和增殖增加。 Wnt/PCP 对于胚胎发育至关重要过程，它调节细胞粘附和迁移。 Wnt/PCP 信号在肿瘤中的新兴作用恶性肿瘤巩固了反复出现的主题，即肿瘤重新激活发育程序以促进其发展攻击行为。 Wnt/PCP 通路成分的表达模式强烈表明 GBM 肿瘤参与促进侵袭性和治疗耐药性的途径，强调了更深层次的观念了解 GBM 中的 Wnt/PCP 可能会发现新的治疗方法。驱动的假设拟议的研究表明，Wnt/PCP 信号传导直接导致 GBM 的恶性特性，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 信号传导利用细胞、分子和机制驱动 GBM 恶性特性的机制生化技术，重点关注 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来确定 PCP 成分的程度导致 GBM 对靶向治疗产生耐药性。将检查体外研究结果在体内的重现在具体目标 3 中，使用 GBM 的原位和患者来源的异种移植小鼠模型。成功者该项目的完成将巩固 Wnt/PCP 通路在 GBM 恶性肿瘤中的参与，并揭示该疾病治疗干预的新靶点。