Elucidating the role of Perilipin-2-mediated lipid droplet formation in supporting glioblastoma pathogenesis
阐明 Perilipin-2 介导的脂滴形成在支持胶质母细胞瘤发病机制中的作用
基本信息
- 批准号:452142590
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:WBP Position
- 财政年份:2020
- 资助国家:德国
- 起止时间:2019-12-31 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Glioblastoma is the most common and aggressive form of malignant brain tumor in adults, for which novel and more efficient therapies are warranted. The microenvironment of glioblastoma is characterized by high levels oxidative stress, which exerts a selective pressure on tumor cells to form adaptive mechanisms to these adverse conditions. Ultimately, this may result in the selection of more aggressive tumor subclones that are resistant to radio/chemotherapy, whose mechanisms of action rely on the induction of oxidative stress. Thus, understanding the molecular adaptations of glioblastoma cells to oxidative stress could potentially reveal vulnerabilities that can be targeted therapeutically. It has recently been described that one aspect of lipid metabolism- the formation of lipid droplets, serves a pro-tumorigenic function in many cancers including glioblastoma. However, the mechanisms underlying this function are not described. Notably, we discovered that established human glioblastoma cell lines contained high levels of lipid droplets. In parallel, we observed that the gene encoding an essential lipid droplet coat protein, Perilipin-2 (PLIN2) was significantly upregulated in tumor tissue from multiple cohorts of glioma and glioblastoma patients, as compared to normal brain tissue. More significantly, preliminary analyses of these public databases revealed that high levels of PLIN2 expression was correlated with poorer overall survival in glioblastoma patients, suggesting that PLIN2 was a clinically relevant factor for poor prognosis. Our preliminary findings also showed that PLIN2 might play a role in the adaptation of tumor cells to oxidative stress, since treatment of these cells with exogenous oxidative stress increased both PLIN2 expression and number of lipid droplets, while knockdown of PLIN2 expression sensitized cells to such treatment. Here, we propose to study in detail the biological function and clinical relevance of PLIN2-mediated lipid droplets in GBM. First, we will determine how PLIN2-mediated lipid droplets support glioblastoma tumorigenicity in vitro, and elucidate the precise molecular mechanisms by which they protect glioblastoma cells against oxidative stress. Second, we will delineate the molecular pathways that govern the transcriptional regulation of PLIN2 in glioblastoma cells. Third, we will further explore the clinical relevance of PLIN2 by assessing the potential association between its expression and clinical parameters of large prospective cohorts of glioblastoma patients, as well as the clinical relevance of lipid droplets according to intra-tumor regional heterogeneity. Overall, the proposed project is expected to significantly contribute to our understanding of the role of lipid droplets in the pathogenicity of glioblastoma, and may potentially lead to the uncovering of PLIN2 as a promising therapeutic target.
胶质母细胞瘤是成年人中最常见和最具侵袭性的恶性脑肿瘤,需要新的更有效的治疗方法。胶质母细胞瘤的微环境的特征在于高水平的氧化应激,其对肿瘤细胞施加选择性压力以形成对这些不利条件的适应机制。最终,这可能导致选择对放射/化学疗法具有抗性的更具侵袭性的肿瘤亚克隆,其作用机制依赖于氧化应激的诱导。因此,了解胶质母细胞瘤细胞对氧化应激的分子适应性可能会揭示出可用于治疗的脆弱性。最近已经描述了脂质代谢的一个方面-脂滴的形成,在包括胶质母细胞瘤在内的许多癌症中起到促肿瘤发生的作用。然而,这一功能背后的机制没有描述。值得注意的是,我们发现已建立的人胶质母细胞瘤细胞系含有高水平的脂滴。同时,我们观察到,与正常脑组织相比,编码必需脂滴外壳蛋白的基因,周磷脂-2(PLIN 2)在来自多个胶质瘤和胶质母细胞瘤患者队列的肿瘤组织中显著上调。更重要的是,这些公共数据库的初步分析显示,PLIN 2的高表达水平与胶质母细胞瘤患者的总体生存率较差相关,表明PLIN 2是预后不良的临床相关因素。我们的初步研究结果还表明,PLIN 2可能在肿瘤细胞适应氧化应激中发挥作用,因为用外源性氧化应激处理这些细胞增加了PLIN 2表达和脂滴数量,而PLIN 2表达的敲低使细胞对这种处理敏感。在这里,我们建议详细研究PLIN 2介导的脂滴在GBM中的生物学功能和临床相关性。首先,我们将确定PLIN 2介导的脂滴如何在体外支持胶质母细胞瘤致瘤性,并阐明它们保护胶质母细胞瘤细胞免受氧化应激的精确分子机制。第二,我们将描述胶质母细胞瘤细胞中PLIN 2转录调控的分子途径。第三,我们将通过评估PLIN 2的表达与胶质母细胞瘤患者的大型前瞻性队列的临床参数之间的潜在关联,以及根据肿瘤内区域异质性的脂滴的临床相关性,进一步探索PLIN 2的临床相关性。总的来说,拟议的项目预计将大大有助于我们了解脂滴在胶质母细胞瘤致病性中的作用,并可能导致PLIN 2作为一个有前途的治疗靶点的发现。
项目成果
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Dr. Jonathan Kah Meng Lim, Ph.D.其他文献
Dr. Jonathan Kah Meng Lim, Ph.D.的其他文献
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