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

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

doi:10.1093/neuonc/noae182

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

Neuro Oncol. 2024 Sep 9:noae182. doi: 10.1093/neuonc/noae182. Online ahead of print.

Authors

Zhenyi An¹, Qi-Wen Fan¹, Linyu Wang¹, Hiroyuki Yoda¹, Megumi J Barata¹, David Jimenez-Morales^{2

3

4

5}, Joanna J Phillips^{6

7}, Danielle L Swaney^{2

3

4

5}, Erica Stevenson^{2

3

4

5}, Ethan Lee⁸, Nevan Krogan^{2

3

4

5}, William A Weiss^{1

6

7

9

10}

Affiliations

¹ Department of Neurology, University of California, San Francisco, CA 94158 USA.
² Quantitative Biosciences Institute (QBI), University of California, San Francisco, CA, 94158, USA.
³ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, 94158, USA.
⁴ Deparment of Cellular and Molecular Pharmacology, University of California San Francisco, CA, 94158, USA.
⁵ J. David Gladstone Institutes, San Francisco, CA 94158, USA.
⁶ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA.
⁷ Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
⁸ Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
⁹ Brain Tumor Research Center, University of California, San Francisco, CA 94158, USA.
¹⁰ Department of Pediatrics, University of California, San Francisco, CA 94158, USA.

PMID: 39248287
DOI: 10.1093/neuonc/noae182

Abstract

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.

Keywords: EGFR; EGFRvIII; Glioblastoma; ROCK2; TLR2.

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