@article{6ae8ce6d8ce949d6879fdd991381823b,
title = "EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation",
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.",
author = "Gao Guo and Ke Gong and Nicole Beckley and Yue Zhang and Xiaoyao Yang and Rati Chkheidze and Hatanpaa, {Kimmo J.} and Tomas Garzon-Muvdi and Prasad Koduru and Arifa Nayab and Jennifer Jenks and Sathe, {Adwait Amod} and Yan Liu and Chao Xing and Wu, {Shwu Yuan} and Chiang, {Cheng Ming} and Bipasha Mukherjee and Sandeep Burma and Bryan Wohlfeld and Toral Patel and Bruce Mickey and Kalil Abdullah and Michael Youssef and Edward Pan and Gerber, {David E.} and Shulan Tian and Sarkaria, {Jann N.} and McBrayer, {Samuel K.} and Dawen Zhao and Habib, {Amyn A.}",
note = "Funding Information: This work was supported in part by funding from the Department of Veteran{\textquoteright}s Affairs (grant no. 2I01BX002559-08) and the National Institutes of Health (grant nos 1R01CA244212-01A1 and 1R01NS119225-01A1) to A.A.H. D.E.G. is supported by a National Cancer Institute (NCI) Midcareer Investigator Award in Patient-Oriented Research (grant no. K24CA201543-01). S.B. is supported by grants from the National Institutes of Health (grant nos R01CA258381 and R01CA246807) and the National Aeronautics and Space Administration (grant no. 80NSSC20K0732). C.-M.C.{\textquoteright}s research is supported by NIH grant no. 1RO1CA251698 and CPRIT grant no. RP190077. D.Z. was supported by NIH grant no. R01 CA194578, S.K.M. is supported by awards from the Cancer Prevention and Research Institute of Texas (grant no. RR190034) and the NCI (grant no. K22CA237752). Research reported in this publication was supported in part by the Harold C. Simmons Comprehensive Cancer Center{\textquoteright}s Biomarker Research Core, which are supported by NCI Cancer Center Support Grant 1P30 CA142543–03. J.N.S. was supported by the MIT/Mayo Physical Sciences Center for Drug Distribution and Efficacy in Brain Tumours (grant no. U54CA210180). We acknowledge NIH shared instrumentation grant no. 1S10OD023552-01 that funded the MRI equipment. We thank S. -Y. Cheng (Northwestern University) for the GSC11 cells. We thank D. -H. Kim (Johns Hopkins University) for advice on the use of patterned nanosurfaces. Funding Information: This work was supported in part by funding from the Department of Veteran{\textquoteright}s Affairs (grant no. 2I01BX002559-08) and the National Institutes of Health (grant nos 1R01CA244212-01A1 and 1R01NS119225-01A1) to A.A.H. D.E.G. is supported by a National Cancer Institute (NCI) Midcareer Investigator Award in Patient-Oriented Research (grant no. K24CA201543-01). S.B. is supported by grants from the National Institutes of Health (grant nos R01CA258381 and R01CA246807) and the National Aeronautics and Space Administration (grant no. 80NSSC20K0732). C.-M.C.{\textquoteright}s research is supported by NIH grant no. 1RO1CA251698 and CPRIT grant no. RP190077. D.Z. was supported by NIH grant no. R01 CA194578, S.K.M. is supported by awards from the Cancer Prevention and Research Institute of Texas (grant no. RR190034) and the NCI (grant no. K22CA237752). Research reported in this publication was supported in part by the Harold C. Simmons Comprehensive Cancer Center{\textquoteright}s Biomarker Research Core, which are supported by NCI Cancer Center Support Grant 1P30 CA142543–03. J.N.S. was supported by the MIT/Mayo Physical Sciences Center for Drug Distribution and Efficacy in Brain Tumours (grant no. U54CA210180). We acknowledge NIH shared instrumentation grant no. 1S10OD023552-01 that funded the MRI equipment. We thank S. -Y. Cheng (Northwestern University) for the GSC11 cells. We thank D. -H. Kim (Johns Hopkins University) for advice on the use of patterned nanosurfaces. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = aug,
doi = "10.1038/s41556-022-00962-4",
language = "English (US)",
volume = "24",
pages = "1291--1305",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "8",
}