The role and mechanism of necrosis in glioblastoma

坏死在胶质母细胞瘤中的作用和机制

• 批准号: 10097263
• 负责人: Wei Li
• 金额: $ 39.35万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10097263
• 关键词: Allografting; Anatomy; Area; Automobile Driving; Biological Process; Cell Death; Cell Line; Cells; Clinical; Coenzyme A Ligases; Cytoplasmic Granules; Development; Diagnostic; Extensive Necrosis; Family member; Gene Expression; Genes; Genetic Transcription; Glioblastoma; Glioma; Goals; Human; Hypoxia; In Vitro; Iron; Lead; Lipid Peroxides; Malignant - descriptor; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchymal Differentiation; Modeling; Mus; Nature; Necrosis; Necrosis Induction; Neutrophil Infiltration; Neutrophilic Infiltrate; Outcome; Pathologic; Pathway interactions; Patients; Peroxidases; Pharmacology; Primary Brain Neoplasms; Process; Prognosis; Reduced Glutathione; Reporting; Role; Sampling; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Thrombosis; Transcriptional Coactivator with PDZ-Binding Motif; Xenograft Model; base; cell killing; cytokine; diagnostic biomarker; experience; experimental study; genetic approach; genetic signature; glutathione peroxidase; in vivo; molecular pathology; mouse model; neoplastic cell; nerve stem cell; neutrophil; novel; programs; targeted treatment; therapeutic target; transcriptome; treatment response; tumor; tumor hypoxia; tumor microenvironment; tumor progression

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 unclear how GBM MES differentiation is achieved. Recent anatomically based transcriptome studies found that tumor cells associated with the necrotic region have higher expression of the MES signature genes, suggesting that the necrotic tumor microenvironment may contribute to MES differentiation and could be exploited as a therapeutic target. The goal of this project is to mechanistically and functionally study GBM necrosis, and identify vulnerabilities of GBM MES progression for therapeutics. We have established the follow premise for the proposed studies. First, we have developed novel pathologically relevant GBM mouse models showing MES differentiation and extensive necrosis. Second, we identified ferroptosis as a novel mechanism for GBM necrosis. Third, in both patient GBM samples and mouse models, we found that the necrotic tumor areas are infiltrated by neutrophils. Our studies suggested that these tumor-associated neutrophils (TANs) are necessary and sufficient to induce tumor cell ferroptosis. Furthermore, we found that ferroptosis and TANs are associated with the hypoxic tumor microenvironment. We hypothesize that GBM necrosis occurs through neutrophil-triggered ferroptosis, and this process is orchestrated by the hypoxic tumor microenvironment. We further hypothesize that ferroptosis could promote tumor progression and be targeted for therapeutic purposes. We propose the following three specific aims: 1) to determine the mechanism of tumor cell ferroptosis induced by TANs; 2) to determine the role of hypoxic tumor microenvironment in tumor cell ferroptosis; 3) to demonstrate the role of ferroptosis in GBM progression and evaluate therapeutic effects of ferroptosis blockade. We will employ a panel of established human GBM cell lines, newly isolated human GBM cells, and mouse GBM models. GBM necrosis is a diagnostic hallmark, predicts tumor aggressiveness, and has deleterious effects on treatments. The nature and mechanism of cell death associated with this necrosis remain obscure. In addition, whether tumor necrosis blockade could benefit therapies is still unknown. By establishing the GBM models faithfully recapitulating the extent of necrosis observed in GBM patients and identification of ferroptosis as the underlying mechanism of tumor necrosis, this proposal will reveal vulnerabilities of GBM MES progression, which could be a novel avenue for GBM therapeutics.

项目概要 胶质瘤是主要的原发性脑肿瘤，其中胶质母细胞瘤（GBM）是最常见且最具侵袭性的 形式。这些肿瘤的传统治疗效果不佳，需要基于以下基础的靶向治疗： 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）组恶性程度最高。目前尚不清楚 GBM MES 如何 实现差异化。最近基于解剖学的转录组研究发现，肿瘤细胞与 具有坏死区域的 MES 特征基因表达较高，表明坏死肿瘤 微环境可能有助于 MES 分化，并可作为治疗靶点。目标 该项目的目的是从机制和功能上研究 GBM 坏死，并识别 GBM MES 的漏洞 治疗的进展。我们为拟议的研究建立了以下前提。首先，我们有 开发了新的病理相关 GBM 小鼠模型，显示 MES 分化和广泛坏死。 其次，我们确定铁死亡是 GBM 坏死的一种新机制。第三，在两个患者 GBM 样本中 和小鼠模型中，我们发现坏死的肿瘤区域被中性粒细胞浸润。我们的研究表明 这些肿瘤相关中性粒细胞（TAN）对于诱导肿瘤细胞铁死亡是必要且充分的。 此外，我们发现铁死亡和 TAN 与缺氧的肿瘤微环境有关。我们 假设 GBM 坏死是通过中性粒细胞引发的铁死亡而发生的，并且该过程是精心策划的 受肿瘤微环境缺氧的影响。我们进一步假设铁死亡可以促进肿瘤 进展并成为治疗目的的目标。我们提出以下三个具体目标：1） 确定TAN诱导肿瘤细胞铁死亡的机制； 2）确定缺氧肿瘤的作用 肿瘤细胞铁死亡的微环境； 3）证明铁死亡在GBM进展中的作用和 评估铁死亡阻断的治疗效果。我们将采用一组已建立的人类 GBM 细胞系， 新分离的人类 GBM 细胞和小鼠 GBM 模型。预测 GBM 坏死是一个诊断标志 肿瘤的侵袭性，并对治疗产生有害影响。细胞死亡的性质和机制 与这种坏死相关的因素仍不清楚。此外，肿瘤坏死阻断是否可以获益？ 治疗方法仍未知。通过建立忠实再现坏死程度的 GBM 模型 在 GBM 患者中观察到，并将铁死亡鉴定为肿瘤坏死的潜在机制，这 该提案将揭示 GBM MES 进展的弱点，这可能是 GBM 的新途径 疗法。