Bimodal EGFR signaling in glioblastoma

胶质母细胞瘤中的双峰 EGFR 信号转导

• 批准号: 10363582
• 负责人: AMYN HABIB
• 金额: $ 42.99万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363582
• 关键词: Adult; Animal Model; Automobile Driving; Biological; Cell Proliferation; Cells; Clinical; Cytoskeleton; Data; Dimerization; EGFR Gene Amplification; EGFR inhibition; Epidermal Growth Factor Receptor; FDA approved; Glioblastoma; Glioma; Human; Ligands; MAP3K7 gene; MAP3K7IP1 gene; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Membrane; Modeling; Mutation; Oncogenes; Oncogenic; Pathway interactions; Pattern; Pharmaceutical Preparations; Prognosis; Proliferating; Proteins; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Tertiary Protein Structure; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Transactivation; Tumor Expansion; Tumor Suppressor Proteins; Up-Regulation; blood-brain barrier permeabilization; efficacy evaluation; epidermal growth factor receptor VIII; improved; malignant phenotype; mouse model; mutant; novel; overexpression; rho GTP-Binding Proteins; tumor; tumor progression

Abstract Glioblastoma (GBM) is the most common primary brain cancer in adults. EGFR is expressed in the majority of GBMs and aberrant EGFR signaling is a major driver of the malignant phenotype. Although the EGFR is considered a prime oncogene in GBM, TCGA analysis indicates that in EGFR amplified GBMs, EGFR ligands are tumor suppressive. Our preliminary data also suggest that ligand-activated EGFR is tumor suppressive. The tumor suppressive effects of ligand-activated EGFR result form an unexpected suppression of invasion. We propose that constitutive and ligand-dependent EGFR wild type signaling triggers distinct signaling pathways. Thus, constitutive EGFR signaling promotes invasion while ligand-activated EGFR signaling turns on proliferation and turns off invasion. We elucidate mechanisms underlying EGFR regulation of invasion and identify BIN3, a protein known to influence the cytoskeleton, as a key suppressor of GBM invasion. We also identify the mechanisms and biological significance of ligand-activated EGFR mediated glioma cell proliferation. We examine the relative contribution of proliferation and invasion to tumor size and prognosis in GBM. An improved understanding of mechanisms that drive GBM invasion is critical to improved treatment. Furthermore, we identify tofacitinib as a drug that can activate the tumor suppressor function of EGFR by increasing EGFR ligand, upregulating BIN3 and suppressing GBM invasion. Tofacitinib is a clinically available and FDA approved drug. Our model holds true for GBMs that express EGFR wild type or the mutant EGFRvIII. In Specific Aim 1: We elucidate the role of RTK transactivation in driving invasion or proliferation. We test the hypothesis that constitutive EGFR signaling promotes EGFR invasiveness whereas ligand-induced EGFR signaling blocks it. Constitutive EGFR signaling leads to activation of Met leading to increased invasiveness. We also identify a TAB1-TAK1-NF- B pathway that drives GBM invasion. Ligand-activated EGFR signaling leads to Axl activation and proliferation and decreased GBM invasiveness. In Specific Aim 2: we uncover mechanisms used by EGFR to suppress invasiveness of GBM cells. We test the hypothesis that BIN3 is a major negative regulator of invasion. Ligand-induced EGFR activity upregulates BIN3 and suppresses invasion. We examine the expression patterns of BIN3, BIN3 partners, EGFR and other RTKs networks in GBM. In Specific Aim 3 we examine the biological effects of constitutive vs. ligand induced EGFR–RTK-BIN3 signaling on GBM invasion in an orthotopic mouse model and examine tofacitinib as a treatment that specifically inhibits GBM invasion in ligand-poor GBMs. .

抽象的 胶质母细胞瘤（GBM）是成年人中最常见的原发性脑癌。 EGFR在大多数 GBM和异常的EGFR信号传导是恶性表型的主要驱动力。虽然EGFR是 TCGA分析被认为是GBM中的主要癌基因，表明在EGFR扩增的GBMS中，EGFR配体 肿瘤抑制。我们的初步数据还表明，配体激活的EGFR是抑制肿瘤的。 配体激活的EGFR的肿瘤抑制作用构成了对侵袭的意外抑制。 我们提出，本构和配体依赖性EGFR野生型信号传导触发了不同的信号 途径。那就是构成EGFR信号传导促进侵袭，而配体激活的EGFR信号转动 关于扩散并关闭入侵。我们阐明了EGFR入侵和 识别BIN3是一种已知会影响细胞骨架的蛋白质，是GBM入侵的关键抑制剂。我们也是 确定配体激活EGFR介导的神经胶质瘤细胞的机制和生物学意义 增殖。我们研究了增殖和侵袭对肿瘤大小和预后的相对贡献 GBM。对驱动GBM入侵的机制的改进理解对于改善治疗至关重要。 此外，我们将Tofacitinib鉴定为可以通过 增加EGFR配体，上调BIN3并抑制GBM入侵。 tofacitinib是临床上可用的 和FDA批准的药物。我们的模型适用于表达EGFR野生型或突变体的GBM egfrviii。在特定目标1中：我们阐明了RTK反式激活在驱动侵袭或增殖中的作用。 我们测试了本构型EGFR信号传导促进EGFR侵入性的假设，而配体诱导的 EGFR信号会阻止它。构型EGFR信号导致MET激活导致增加 侵入性。我们还确定了驱动GBM入侵的TAB1-TAK1-NF-B途径。配体激活 EGFR信号传导导致AXL激活和增殖，并提高GBM的侵入性。在特定目标2中： 我们发现EGFR使用的机制抑制GBM细胞的侵入性。我们检验了以下假设 BIN3是入侵的主要负面调节剂。配体诱导的EGFR活性上调了BIN3和 抑制入侵。我们检查了BIN3，BIN3合作伙伴，EGFR和其他RTK的表达模式 GBM中的网络。在特定目的3中，我们检查了构型与配体诱导的生物学效应 OGFR – RTK-BIN3信号在正常小鼠模型中GBM侵袭和tofacitinib作为一种 专门抑制GBM侵入配体GBM的GBM侵袭的治疗。 。