EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation

Gao Guo, Ke Gong, Nicole Beckley, Yue Zhang, Xiaoyao Yang, Rati Chkheidze, Kimmo J. Hatanpaa, Tomas Garzon-Muvdi, Prasad Koduru, Arifa Nayab, Jennifer Jenks, Adwait Amod Sathe, Yan Liu, Chao Xing, Shwu Yuan Wu, Cheng Ming Chiang, Bipasha Mukherjee, Sandeep Burma, Bryan J Wohlfeld, Toral PatelBruce Mickey, Kalil Abdullah, Michael Youssef, Edward Pan, David E. Gerber, Shulan Tian, Jann N. Sarkaria, Samuel K. McBrayer, Dawen Zhao, Amyn A. Habib

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1–TAK1–NF-κB–EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3.

Original languageEnglish (US)
Pages (from-to)1291-1305
Number of pages15
JournalNature cell biology
Volume24
Issue number8
DOIs
StatePublished - Aug 2022

ASJC Scopus subject areas

  • Cell Biology

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