表皮生长因子受体和表皮生长因子受体vIII协同宿主防御途径，促进胶质母细胞瘤的进展。

IF 16.4 1区医学 Q1 CLINICAL NEUROLOGY Neuro-oncology Pub Date : 2024-09-09 DOI:10.1093/neuonc/noae182

Zhenyi An, Qi-Wen Fan, Linyu Wang, Hiroyuki Yoda, Megumi J Barata, David Jimenez-Morales, Joanna J Phillips, Danielle L Swaney, Erica Stevenson, Ethan Lee, Nevan Krogan, William A Weiss

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引用次数: 0

摘要

背景：表皮生长因子受体和表皮生长因子受体vIII（表皮生长因子受体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遗传病变：我们利用磷酸蛋白组学、RNA测序、TCGA数据以及胶质母细胞瘤细胞培养和小鼠模型研究了表皮生长因子受体和表皮生长因子受体vIII介导的信号转导：结果：我们发现表皮生长因子受体（EGFR）和表皮生长因子受体vIII能刺激先天性免疫防御受体Toll样受体2（TLR2）；敲除TLR2能显著提高正位胶质母细胞瘤异种移植物的存活率。表皮生长因子受体和表皮生长因子受体vIII以配体无关的方式激活TLR2，促进肿瘤生长和免疫逃避。我们的研究表明，表皮生长因子受体和表皮生长因子受体vIII合作激活了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调节恶性进展：总之，我们的研究结果表明，表皮生长因子受体和表皮生长因子受体vIII通过ROCK2和下游WNT-β-catenin/TLR2信号通路合作驱动肿瘤进展。

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EGFR and EGFRvIII coopt host defense pathways, promoting progression in glioblastoma.

Background: Co-amplification of 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 and 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.

Conclusion: Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-β-catenin/TLR2 signaling pathways.

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来源期刊

Neuro-oncology 医学-临床神经学

CiteScore

27.20

自引率

6.30%

发文量

1434

审稿时长

3-8 weeks

期刊介绍： Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.