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

• 批准号: 9907522
• 负责人: Courtney Anne Dreyer
• 金额: $ 3.77万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/9907522
• 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; Diagnostic; 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; Treatment Efficacy; WNT Signaling Pathway; Xenograft procedure; arm; brain tissue; cell behavior; cell growth; cell motility; chemotherapy; clinical efficacy; 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; novel therapeutics; planar cell polarity; polarized cell; programs; receptor; targeted treatment; temozolomide; therapy resistant; treatment strategy; tumor; tumor growth

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.

项目摘要 胶质母细胞瘤多形（GBM）是恶性脑癌的最常见形式，并且具有高度侵略性， 经常性，难以治疗。 GBM细胞的高度浸润性质降低了 手术，虽然已经探索了更有效的患者监管疗法的前景，但此类策略 到目前为止，由于肿瘤始终具有高度抗性，因此已经失败了。 Wnt/Planar细胞极性（PCP）是非 - 规范Wnt信号通路，促进了全局方向提示，以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计划以促进其 侵略性行为。 Wnt/PCP途径成分的表达模式强烈表明GBM肿瘤 参与促进侵入性和治疗性抗性的途径，强调了更深入的观念 了解GBM中WNT/PCP的理解可能会发现新颖的治疗方法。推动的假设 拟议的研究是Wnt/PCP信号传导直接有助于GBM的恶性特性，包括 增殖，运动，侵入性和治疗性抗性。具体目标1将严格地描述 Wnt/PCP信号传导使用细胞，分子和 生化技术，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来确定PCP组件的程度 有助于GBM对靶向治疗剂的抗性。将检查体内体外发现的概括 在特定的目标3中，使用GBM的原位和患者衍生的异种移植小鼠模型。成功 该项目的完成将巩固WNT/PCP途径在GBM恶性肿瘤中的参与，并揭示 治疗干预对疾病的新靶标。