Journal
NATURE CELL BIOLOGY
Volume 24, Issue 8, Pages 1291-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-022-00962-4
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Funding
- Department of Veteran's Affairs [2I01BX002559-08]
- National Institutes of Health [R01CA258381, R01CA246807, 1R01CA244212-01A1, 1R01NS119225-01A1]
- National Cancer Institute (NCI) Midcareer Investigator Award in Patient-Oriented Research [K24CA201543-01]
- National Aeronautics and Space Administration [80NSSC20K0732]
- NIH [1S10OD023552-01, 1RO1CA251698]
- CPRIT grant [RP190077]
- Cancer Prevention and Research Institute of Texas [RR190034]
- NCI [K22CA237752]
- Harold C. Simmons Comprehensive Cancer Center's Biomarker Research Core - NCI Cancer Center Support Grant [1P30 CA142543-03]
- MIT/Mayo Physical Sciences Center for Drug Distribution and Efficacy in Brain Tumours [U54CA210180]
- NCI Cancer Center Support Grant [1P30 CA142543-03]
- NIH shared instrumentation grant [1S10OD023552-01]
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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.
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.
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