Abstract: Activated by its single ligand, hepatocyte growth factor (HGF), the receptor tyrosine kinase MET is pivotal in promoting glioblastoma stem cell (GSC) self-renewal, invasiveness and tumorigenicity. Nevertheless, HGF/MET-targeted therapy has shown limited clinical benefits in glioblastoma patients, suggesting hidden mechanisms of MET signalling in glioblastoma. Here, we show that circular MET RNA (circMET) encodes a 404 amino acid novel MET variant (MET404) facilitated by the N6-methyladenosine (m6A) reader YTHDF2. Genetic ablation of circMET inhibited MET404 expression in mice and attenuated MET signalling. Conversely, MET404 knock-in plus P53 knock-out in mouse astrocytes initiated glioblastoma tumorigenesis and shortened 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 glioblastoma patients, indicating its clinical relevance. Targeting MET404 through a neutralizing antibody or genetic ablation reduced glioblastoma tumorigenicity in vitro and in vivo, with combinatorial benefits when a traditional MET inhibitor was added. Overall, we identified a novel MET variant that promotes glioblastoma tumorigenicity, offering a potential new therapeutic strategy for glioblastoma.
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