Activated by its single ligand, hepatocyte growth factor (HGF), the receptor tyrosine kinase MET is pivotal in promoting glioblastoma (GBM) stem cell self-renewal, invasiveness and tumorigenicity. Nevertheless, HGF/MET-targeted therapy has shown limited clinical benefits in GBM patients, suggesting hidden mechanisms of MET signalling in GBM. Here, we show that circular MET RNA (circMET) encodes a 404-amino-acid MET variant (MET404) facilitated by the N⁶-methyladenosine (m⁶A) reader YTHDF2. Genetic ablation of circMET inhibits MET404 expression in mice and attenuates MET signalling. Conversely, MET404 knock-in (KI) plus P53 knock-out (KO) in mouse astrocytes initiates GBM tumorigenesis and shortens the overall survival. MET404 directly interacts with the MET β subunit and forms a constitutively activated MET receptor whose activity does not require HGF stimulation. High MET404 expression predicts poor prognosis in GBM patients, indicating its clinical relevance. Targeting MET404 through a neutralizing antibody or genetic ablation reduces GBM tumorigenicity in vitro and in vivo, and combinatorial benefits are obtained with the addition of a traditional MET inhibitor. Overall, we identify a MET variant that promotes GBM tumorigenicity, offering a potential therapeutic strategy for GBM patients, especially those with MET hyperactivation.

受体酪氨酸激酶 MET 由其单一配体肝细胞生长因子 (HGF) 激活，在促进胶质母细胞瘤 (GBM) 干细胞自我更新、侵袭性和致瘤性方面发挥着关键作用。然而，HGF/MET 靶向治疗在 GBM 患者中显示出有限的临床益处，这表明 GBM 中 MET 信号传导的隐藏机制。^{在这里，我们展示了环状 MET RNA (circMET) 编码由 N 6} -甲基腺苷 (m ⁶ A)阅读器 YTHDF2 促进的 404 个氨基酸 MET 变体 (MET404) 。circMET 的基因消除会抑制小鼠体内 MET404 的表达并减弱 MET 信号传导。相反，小鼠星形胶质细胞中的 MET404 敲入 (KI) 加上P53敲除 (KO) 会引发 GBM 肿瘤发生并缩短总体生存期。MET404 直接与 MET β 亚基相互作用，形成组成型激活的 MET 受体，其活性不需要 HGF 刺激。MET404 高表达预示 GBM 患者预后不良，表明其临床相关性。通过中和抗体或基因消融靶向 MET404 可降低 GBM 体外和体内致瘤性，并且通过添加传统 MET 抑制剂可以获得组合益处。总的来说，我们发现了一种促进 GBM 致瘤性的 MET 变异，为 GBM 患者，特别是 MET 过度激活的患者提供了潜在的治疗策略。