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

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.

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.

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.

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.