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

Nature cell biology 2022 Aug

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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. © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

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 Wohlfeld, Toral Patel, Bruce Mickey, Kalil Abdullah, Michael Youssef, Edward Pan, David E Gerber, Shulan Tian, Jann N Sarkaria, Samuel K McBrayer, Dawen Zhao, Amyn A Habib. EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation. Nature cell biology. 2022 Aug;24(8):1291-1305