EML4-ALK fusion rewires transcriptomic, miRNA, and CAF-associated programs in non-small cell lung cancer.

PURPOSE: This study presents an integrative analysis of paired mRNA/miRNA expression and tumor microenvironment features to characterize the molecular landscape associated with EML4-ALK fusion status in non-small cell lung cancer (NSCLC).

METHODS

Using TCGA-derived fusion-positive and fusion-negative NSCLC cohorts, we compared three complementary layers of tumor biology: transcriptomic architecture, miRNA-mRNA regulatory networks, and immune-stromal composition.

RESULTS

Fusion-positive tumors exhibited a distinct molecular program characterized by metabolic and proteostasis reprogramming, including glycolytic and N-glycan biosynthetic pathways linked to endoplasmic reticulum protein processing and export. Relative to fusion-negative tumors, they also showed reduced stromal infiltration and attenuation of extracellular matrix, adhesion, calcium signaling, and cytokine-related transcriptional programs. Integrative miRNA analysis identified a fusion-associated, miR-3065-centered regulatory hub with predicted extracellular matrix- and adhesion-related targets,including PDGFRB, CTSK, COL4A2, SPARC, FBN1, and LUM, whereas fusion-negative tumorsshowed miRNA network alterations associated with proliferative and ciliary programs. Tumormicroenvironment analysis further distinguished the groups, with fusion-positive tumors showing reduced cancer-associated fibroblast infiltration.

CONCLUSION

These findings characterize distinct molecular and microenvironmental features associated with EML4-ALK fusion-positive NSCLC and identify candidate regulatory networks and biomarkers that, pendingvalidation, may inform subtype-specific therapeutic stratification.