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

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-kappa B-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. Guo et al. show that ligand-induced EGFR activation suppresses invasion by upregulating BIN3 and inhibiting DOCK7-regulated Rho GTPase activity in EGFR-amplified glioblastoma, which is in contrast to the known oncogenic role for EGFR signalling.

Automated summary

In this study, the authors discovered a new tumor-suppressive function of EGFR in EGFR-amplified glioblastomas. They found that the level of EGFR ligands can shift the role of EGFR from an oncogene to a tumor suppressor, influencing the prognosis of the disease. Increasing the level of EGFR ligands can activate the tumor-suppressive function of EGFR, resulting in inhibited tumor growth and invasion.