Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, School of Basic Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China.
Nat Cell Biol. 2022 Aug;24(8):1291-1305. doi: 10.1038/s41556-022-00962-4. Epub 2022 Aug 1.
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.
表皮生长因子受体（EGFR）是一种主要的致癌基因，在胶质母细胞瘤中经常扩增。在这里，我们证明了 EGFR 配体调控的 EGFR 扩增胶质母细胞瘤中 EGFR 的一个新的肿瘤抑制功能。组成性 EGFR 信号通过激活 TAB1-TAK1-NF-κB-EMP1 途径促进侵袭，导致肿瘤体积增大和原位模型中生存率降低。配体激活的 EGFR 通过上调 BIN3 促进增殖，令人惊讶的是抑制了 DOCK7 调节的 Rho GTPase 途径，导致小的过度增殖性非侵袭性肿瘤和生存率提高。来自癌症基因组图谱的数据表明，在 EGFR 扩增的胶质母细胞瘤中，低水平的 EGFR 配体预示着更差的预后，而高水平的 EGFR 配体预示着更好的预后。因此，增加 EGFR 配体水平通过抑制侵袭将 EGFR 的作用从致癌基因转变为 EGFR 扩增胶质母细胞瘤中的肿瘤抑制因子。使用托法替尼可以激活 EGFR 的肿瘤抑制功能，托法替尼通过增加 EGFR 配体水平和上调 BIN3 来抑制侵袭。
