Targeting MUC16 to Reverse Anoikis Resistance: A Promising Strategy for Metastatic Lung Adenocarcinoma Therapy

Background: Although the mucin glycoprotein MUC16 is well established as an oncogenic biomarker in ovarian cancer, its mechanistic contribution to lung adenocarcinoma (LUAD) remains poorly defined. This study integrates multi-omics profiling and functional validation to uncover MUC16 as a novel determinant of detachment-induced survival in LUAD. Methods: Transcriptomic and clinical data from TCGA-LUAD and GEO cohorts were analyzed to identify differentially expressed anoikis-related genes. Functional enrichment, GSVA, and network analyses delineated key signaling pathways. Multi-omic integration including copy-number, methylation, immune infiltration, and pharmacogenomic data was used to explore upstream regulatory mechanisms. Experimental assays were performed in A549 cells following siRNA-mediated MUC16 silencing, assessed by qRT-PCR, wound-healing, and transwell migration analyses. Results: Nineteen overlapping anoikis-related differentially expressed genes (ARDEGs) were identified, with MUC16 displaying the most significant upregulation in LUAD and a strong association with poor overall survival (HR = 1.04, p < 0.001). Pathway enrichment indicated activation of cell-adhesion, Hippo, and PI3K–AKT signaling networks. Multi-omic analysis revealed that promoter hypomethylation and copy-number gain drive MUC16 overexpression, which correlates with reduced cytotoxic T-cell infiltration and an immunosuppressive microenvironment. Functionally, MUC16 knockdown diminished cell adhesion, migration, and wound closure, consistent with loss of detachment survival capacity. Conclusion: This work establishes MUC16 as a mechanistic mediator of metastatic competence in LUAD, acting through adhesion-linked PI3K–AKT signaling to protect tumor cells from detachment-induced apoptosis. Therapeutic inhibition of MUC16 may restore apoptotic susceptibility and suppress metastatic spread in lung cancer.