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
{"title":"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。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Co-amplification of EGFR and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-β-catenin/TLR2 signaling pathways.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"EGFR and EGFRvIII coopt host defense pathways, promoting progression in glioblastoma.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Co-amplification of EGFR and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-β-catenin/TLR2 signaling pathways.</p>\",\"PeriodicalId\":19377,\"journal\":{\"name\":\"Neuro-oncology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":16.4000,\"publicationDate\":\"2024-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuro-oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/neuonc/noae182\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuro-oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/neuonc/noae182","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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.
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.