Metadherin at the invasive front drives OSCC via selective KRT14 regulation

Despite advances in multimodal therapy, effective treatments for aggressive oral squamous cell carcinoma (OSCC) remain limited, underscoring the need for actionable therapeutic targets. Metadherin (MTDH), a stress-responsive gene broadly upregulated in diverse malignancies and proposed as a cancer fitness gene, has not been fully characterized in OSCC. To define its pathological and functional relevance, we integrated analyses of patient specimens, CRISPR/Cas9-mediated loss-of-function models, and transcriptomic profiling. Immunohistochemical evaluation of 100 surgically resected OSCC cases demonstrated spatial heterogeneity of MTDH expression, with enrichment at the invasive front compared with the tumor center. High MTDH expression was significantly associated with non-cohesive invasion patterns. In OSCC cell lines, MTDH knockout suppressed migration and invasion without affecting proliferation or apoptosis, effectively uncoupling invasive capacity from cell growth. Transcriptomic analysis revealed selective transcriptional modulation rather than global gene expression changes. Within this restricted gene repertoire, keratin 14 (KRT14) was consistently downregulated and positively correlated with MTDH expression at both transcript and protein levels. Collectively, these findings identify MTDH as a determinant of OSCC invasion and migration, with KRT14 as a candidate downstream effector, without broadly perturbing global transcription, supporting MTDH as a precision therapeutic target for inhibiting invasion.