{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe MET proto‐oncogene encodes a receptor tyrosine kinase that is activated upon binding its ligand, hepatocyte growth factor (HGF), and normally orchestrates signaling cascades governing cell proliferation, survival, motility, and differentiation. However, when dysregulated—through gene amplification, activating mutations (including exon 14–skipping events), or oncogenic fusion events—MET drives aberrant activation of downstream pathways such as PI3K/AKT and RAS/MAPK. Such alterations contribute directly to malignant transformation and tumor progression in diverse cancers including non–small‐cell lung cancer (NSCLC), hepatocellular carcinoma, and glioblastoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant MET signaling also plays a central role in therapeutic resistance. In NSCLC, for example, subpopulations with MET amplification and HGF‐driven bypass signaling activate ERBB3/PI3K and GAB1 pathways that undermine the efficacy of EGFR tyrosine kinase inhibitors. Similarly, in HER2‐overexpressing breast cancers, increased MET expression can override trastuzumab‐mediated growth suppression by counteracting cell cycle regulatory events. These findings underscore the importance of MET as a mediator of resistance to targeted therapies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "9", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in drug resistance, MET signaling promotes tumor cell invasion and metastasis. Hypoxia‐induced upregulation of MET sensitizes cells to HGF stimulation, thereby enhancing invasive growth. MET‐enriched exosomes derived from highly metastatic melanomas have been shown to “educate” bone marrow progenitors toward a pro‐metastatic state, while compensatory MET activation following VEGF blockade in glioblastoma amplifies invasive and mesenchymal characteristics. Moreover, regulatory mechanisms—ranging from alterations in receptor endocytosis to microRNA‐mediated suppression—further fine‐tune MET’s pro‐migratory effects, underscoring its multifaceted role in reshaping the tumor microenvironment to favor dissemination."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComprehensive genomic analyses have uncovered a spectrum of MET alterations—including exon 14 splice site mutations, gene amplifications, and oncogenic fusion transcripts—that are now being exploited as predictive biomarkers for MET‐targeted therapies such as crizotinib, onartuzumab, and ARQ 197. Beyond its canonical oncogenic functions, MET intersects with diverse regulatory networks: its activity is modulated by microRNAs (for example, miR‑26a and miR‑34a), tempered by tumor suppressors such as GPx3, and even extends to noncanonical roles such as supporting neutrophil chemoattraction, interfering with apoptosis via sequestration of the Fas receptor, and serving as a coreceptor in viral internalization. Notably, genetic variations in MET have also been associated with neurodevelopmental disorders, illustrating its broader biological significance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jeffrey A Engelman, Kreshnik Zejnullahu, Tetsuya Mitsudomi, et al. 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