The role of NONO in TAZ-driven glioma malignant transformation

NONO在TAZ驱动的胶质瘤恶性转化中的作用

• 批准号: 10231202
• 负责人: Wei Li
• 金额: $ 33.31万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231202
• 关键词: Allografting; Automobile Driving; Binding Proteins; Biological Process; Brain; CD44 gene; Cell Line; Cell Nucleus; Cell model; Cells; Complex; Couples; DNA; DNA-Binding Proteins; Development; Elements; Environment; Family member; Gene Expression; Genes; Genetic Transcription; Glioblastoma; Glioma; Goals; Human; Immune; In Vitro; Infiltration; Knock-out; Maintenance; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchymal Differentiation; Microglia; Modeling; Mus; Necrosis; Neuroglia; Neurons; Nuclear Protein; Oncogenic; Outcome; Pathogenesis; Pharmacology; Physiological; Physiology; Primary Brain Neoplasms; Process; Prognosis; RNA Polymerase II; RNA Processing; Regulation; Reporting; Role; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Transcription Coactivator; Transcriptional Coactivator with PDZ-Binding Motif; Transcriptional Regulation; Tumor-associated macrophages; Xenograft Model; base; cytokine; diagnostic biomarker; experimental study; genetic approach; in vivo; inhibitor/antagonist; molecular pathology; mouse model; nerve stem cell; novel; pre-clinical; programs; recruit; targeted treatment; therapeutic target; therapy resistant; treatment response; tumor

Project Summary Gliomas are major primary brain tumors, of which glioblastomas (GBM) are the most common and aggressive forms. The poor outcome of traditional treatment for these tumors demands targeted therapies based on identified mechanisms that drive tumor development. Molecular pathology has classified GBM into subtypes, among which the mesenchymal (MES) group is the most malignant. It is still not clear how GBM MES differentiation is achieved. Recent studies found enrichment of tumor-associated macrophages and microglia (TAMs) in MES GBM, suggesting that TAMs may contribute to MES differentiation and could be exploited as therapeutic targets. Transcriptional coactivator with PDZ-binding motif (TAZ) is one of the three transcriptional regulators in driving the GBM MES gene expression program. Aberrant TAZ activation is associated with MES GBM. The goal of this project is to investigate the role of the TAZ-driven MES transcriptional program during TAMs enrichment in GBM, and identify vulnerabilities of GBM MES progression for therapeutics. The first premise of the project is that we have established two novel TAZ-driven GBM mouse models showing enhanced expression of the MES marker and TAMs infiltration. The second premise is that we have identified the non-POU-domain-containing, octamer-binding protein (NONO) as a novel TAZ-binding protein, which is critical for TAZ-driven gene transcription, TAMs infiltration and GBM progression. The third premise is that NONO expression is markedly increased in GBM compared to lower grade gliomas and is associated with TAZ as well as shorter survival. We hypothesize that aberrant TAZ activation promotes GBM to exploit TAMs for malignant progression, and NONO is important in this process by mediating the TAZ transcriptional activities. We further hypothesize that NONO and TAMs could be targeted for therapeutic purposes. We propose the following three specific aims: 1) to determine the mechanism of TAMs recruitment by TAZ-driven GBM; 2) to demonstrate the mechanism by which NONO regulates the TAZ-driven oncogenic transcriptional program in GBM; 3) to evaluate therapeutic effects of NONO inhibition and TAMs blockade in preclinical TAZ-driven GBM models. We will employ a panel of established human GBM cell lines, newly isolated human GBM cells, and mouse models of GBM. Increasing evidence suggests that TAMs contributes to the pathogenesis and therapeutic resistance of GBM. How TAMs are enriched in MES GBM and whether TAMs blockade could benefit therapies for these tumors is still unknown. By establishing the TAZ-driven GBM models and demonstrating the TAZ-NONO regulatory axis in recruiting TAMs, this proposal will reveal vulnerabilities of TAZ-driven GBM progression. Because NONO appears to be nonessential in normal physiology, the GBM- specific vulnerabilities could be a novel avenue for therapeutics.

项目摘要 胶质瘤是主要的原发性脑肿瘤，其中胶质母细胞瘤（GBM）是最常见和最具侵袭性的 forms.这些肿瘤的传统治疗效果不佳，需要基于以下方面的靶向治疗： 确定了驱动肿瘤发展的机制。分子病理学已将GBM分为亚型， 其中间充质（MES）组是最恶性的。目前尚不清楚GBM是如何 实现了差异化。最近的研究发现肿瘤相关巨噬细胞和小胶质细胞的富集 （TAMs）在MES GBM中的表达，这表明TAMs可能有助于MES分化，并可用作 治疗目标具有PDZ结合基序的转录辅激活因子（TAZ）是三种转录辅激活因子之一， 在驱动GBM MES基因表达程序的调节。TAZ异常激活与MES相关 GBM。本项目的目标是研究TAZ驱动的MES转录程序在细胞凋亡过程中的作用。 GBM中的TAM富集，并鉴定用于治疗的GBM MES进展的脆弱性。第一 该项目的前提是，我们已经建立了两个新的TAZ驱动的GBM小鼠模型， MES标志物的表达增强和TAM浸润。第二个前提是我们已经确定 作为新的TAZ结合蛋白的不含POU结构域的八聚体结合蛋白（NONO）， 对于TAZ驱动的基因转录、TAM浸润和GBM进展至关重要。第三个前提是， 与低级别胶质瘤相比，GBM中NONO表达显著增加，并且与TAZ相关。 以及更短的生存期。我们假设异常的TAZ激活促进GBM利用TAM， 恶性进展，NONO通过介导TAZ转录活性在该过程中是重要的。 我们进一步假设NONO和TAM可以用于治疗目的。我们建议 以下三个具体目标：1）确定TAZ驱动的GBM招募TAM的机制; 2） 证明NONO调节TAZ驱动的致癌转录程序的机制， GBM; 3）评估NONO抑制和TAM阻断在临床前TAZ驱动的GBM中的治疗效果 模型我们将使用一组已建立的人GBM细胞系、新分离的人GBM细胞和人GBM细胞。 GBM的小鼠模型。越来越多的证据表明，TAM有助于发病机制， GBM的治疗抗性。TAM如何在MES GBM中富集以及TAM阻断是否可以 这些肿瘤的有效治疗仍然是未知的。通过建立TAZ驱动的GBM模型， 展示了TAZ-NONO在招募TAM方面的监管轴心，该提案将揭示 TAZ驱动的GBM进展。由于NONO在正常生理中似乎不是必需的，因此GBM- 特定的脆弱性可能是治疗的新途径。