LAUSR

Vasculogenic mimicry (VM), a process in which cancer cells form endothelial cell-independent vascular networks, is a hallmark of tumor aggressiveness in lung adenocarcinoma (LUAD) and supports tumor growth and metastasis. This study aims to identify and validate key genes associated with VM formation in LUAD, and to elucidate their functional roles and clinical significance. Transcriptomic data from LUAD samples were analyzed using differential expression analysis (DEA) and weighted gene co-expression network analysis (WGCNA) to identify VM-associated genes. Machine learning algorithms were applied to refine the selection and identify hub genes. Functional enrichment and immune infiltration analyses were performed. The role of SULF1 in VM was further validated through in vitro and in vivo experiments. We identified 10,810 differentially expressed genes. WGCNA revealed 101 VM-associated genes, predominantly within the “yellow” and “brown” modules. Machine learning pinpointed three key regulators: downregulated decorin (DCN) and upregulated nucleoplasmin 3 (NPM3) and sulfatase 1 (SULF1). Functional enrichment analysis highlighted their involvement in extracellular matrix (ECM) organization and ribosomal pathways. Immune infiltration analysis indicated a positive correlation between DCN and immune cell presence, whereas NPM3 and SULF1 showed negative correlations. Critically, SULF1 overexpression promoted VM formation in vitro by enhancing cell migration and invasion, mediated through the vascular endothelial growth factor (VEGF)/transforming growth factor beta (TGF-β)/Vimentin signaling axis, and accelerated tumor growth in vivo. We identified DCN, NPM3, and SULF1 as key biomarkers of VM in LUAD. SULF1, in particular, plays a central role in driving VM formation and tumor progression. These findings offer novel mechanistic insights and highlight potential therapeutic targets for LUAD treatment.