表皮生长因子受体（EGFR）和表皮生长因子受体变异体III（EGFRvIII）利用宿主防御途径促进胶质母细胞瘤进展。
EGFR and EGFRvIII coopt host defense pathways promoting progression in glioblastoma.
作者信息
An Zhenyi, Fan Qi-Wen, Wang Linyu, Yoda Hiroyuki, Barata Megumi J, Jimenez-Morales David, Phillips Joanna J, Swaney Danielle L, Stevenson Erica, Lee Ethan, Krogan Nevan, Weiss William A
机构信息
Department of Neurology, University of California, San Francisco, California, USA.
J. David Gladstone Institutes, San Francisco, California, USA.
出版信息
Neuro Oncol. 2025 Feb 10;27(2):383-397. doi: 10.1093/neuonc/noae182.
BACKGROUND
Co-amplification of the epidermal growth factor receptor (EGFR) and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma.
METHODS
We used phospho-proteomics, RNA-sequencing, TCGA data, glioblastoma cell culture, and mouse models to study the signal transduction mediated by EGFR and EGFRvIII.
RESULTS
We report that EGFR and EGFRvIII stimulate the innate immune defense receptor Toll-like Receptor 2 (TLR2); and that knockout of TLR2 dramatically improved survival in orthotopic glioblastoma xenografts. EGFR and EGFRvIII activated TLR2 in a ligand-independent manner, promoting tumor growth and immune evasion. We show that EGFR and EGFRvIII cooperate to activate the Rho-associated protein kinase ROCK2, which modulated malignant progression both by activating TLR2 and WNT signaling, and through remodeling the tumor microenvironment.
CONCLUSIONS
Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-β-catenin/TLR2 signaling pathways.
背景
表皮生长因子受体（EGFR）和EGFRvIII（EGFR的一种肿瘤特异性截短突变体）的共扩增是胶质母细胞瘤的标志性基因损伤。
方法
我们使用磷酸化蛋白质组学、RNA测序、TCGA数据、胶质母细胞瘤细胞培养和小鼠模型来研究由EGFR和EGFRvIII介导的信号转导。
结果
我们报告EGFR和EGFRvIII刺激先天性免疫防御受体Toll样受体2（TLR2）；并且TLR2基因敲除显著提高了原位胶质母细胞瘤异种移植模型的生存率。EGFR和EGFRvIII以不依赖配体的方式激活TLR2，促进肿瘤生长和免疫逃逸。我们表明EGFR和EGFRvIII协同激活Rho相关蛋白激酶ROCK2，ROCK2通过激活TLR2和WNT信号以及重塑肿瘤微环境来调节恶性进展。
结论
总之，我们的研究结果表明EGFR和EGFRvIII通过ROCK2和下游WNT-β-连环蛋白/TLR2信号通路协同驱动肿瘤进展。
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