Identification of Basement Membrane-Related Biomarkers in the Progression of Cutaneous Squamous Cell Carcinoma

Basement membrane (BM) breaching is a critical hallmark of cutaneous squamous cell carcinoma (cSCC) invasion. This study aimed to identify novel BM-related genes (BMRGs) to effectively distinguish invasive cSCC from actinic keratosis (AK) and Bowen’s disease (BD), and to identify potential therapeutic targets. Single-cell RNA sequencing was used for BMRGs identification within keratinocytes and fibroblasts clusters. Protein–protein interaction network analysis and Lasso regression were performed for hub BMRGs screening, together with nomogram model construction and validation. In this study, 6–9 central hub BMRGs were identified for each stage during cSCC progression with a good AUC value (>0.8). In keratinocytes, BMRGs such as integrins (ITGB1, ITGA3, ITGA6), laminins (LAMA3, LAMC1), CD44, and FN1 were upregulated in cSCC compared to AK or BD (adjusted p < 0.05); in fibroblasts, BMRGs including ITGB1, ITGAV, LUM, BGN, SDC1, and FN1 were upregulated in cSCC (adjusted p < 0.05), suggesting their collective role in BM breaching and invasion, as well as a higher risk of BD. This study provides novel biological insights into the differentiation of progression pathways from AK or BD to cSCC, as well as potential targets for therapeutic intervention.