Bimodal EGFR signaling in glioblastoma

胶质母细胞瘤中的双峰 EGFR 信号转导

基本信息

  • 批准号:
    10544555
  • 负责人:
  • 金额:
    $ 41.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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. .
摘要

项目成果

期刊论文数量(0)
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AMYN HABIB其他文献

AMYN HABIB的其他文献

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{{ truncateString('AMYN HABIB', 18)}}的其他基金

Bimodal EGFR signaling in glioblastoma
胶质母细胞瘤中的双峰 EGFR 信号转导
  • 批准号:
    10363582
  • 财政年份:
    2022
  • 资助金额:
    $ 41.39万
  • 项目类别:
The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma
Nrf2 在介导胶质母细胞瘤对 EGFR 抑制的抵抗中的作用
  • 批准号:
    10404075
  • 财政年份:
    2020
  • 资助金额:
    $ 41.39万
  • 项目类别:
The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma
Nrf2 在介导胶质母细胞瘤对 EGFR 抑制的抵抗中的作用
  • 批准号:
    10615766
  • 财政年份:
    2020
  • 资助金额:
    $ 41.39万
  • 项目类别:
Interactions between inflammatory and oncogenic signaling pathways in GBM
GBM 炎症和致癌信号通路之间的相互作用
  • 批准号:
    8735239
  • 财政年份:
    2014
  • 资助金额:
    $ 41.39万
  • 项目类别:
Interactions between inflammatory and oncogenic signaling pathways in GBM
GBM 炎症和致癌信号通路之间的相互作用
  • 批准号:
    10266003
  • 财政年份:
    2014
  • 资助金额:
    $ 41.39万
  • 项目类别:
Interactions between inflammatory and oncogenic signaling pathways in GBM
GBM 炎症和致癌信号通路之间的相互作用
  • 批准号:
    9339563
  • 财政年份:
    2014
  • 资助金额:
    $ 41.39万
  • 项目类别:
A Role for RIP1 in Gliomagenesis
RIP1 在神经胶质瘤发生中的作用
  • 批准号:
    8147853
  • 财政年份:
    2009
  • 资助金额:
    $ 41.39万
  • 项目类别:
A Role for RIP1 in Gliomagenesis
RIP1 在神经胶质瘤发生中的作用
  • 批准号:
    8308027
  • 财政年份:
    2009
  • 资助金额:
    $ 41.39万
  • 项目类别:
A Role for RIP1 in Gliomagenesis
RIP1 在神经胶质瘤发生中的作用
  • 批准号:
    7785369
  • 财政年份:
    2009
  • 资助金额:
    $ 41.39万
  • 项目类别:
EGFR MEDIATED APOPTOSIS IN GLIOMAS
EGFR 介导的胶质瘤细胞凋亡
  • 批准号:
    6633249
  • 财政年份:
    1999
  • 资助金额:
    $ 41.39万
  • 项目类别:

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