Pan-cancer landscape of basement membrane: multi-omics research and single-cell sequencing validation

Epithelial carcinoma cells require penetration of the basement membrane (BM) to metastasize. The BM is a thin layer of extracellular matrix beneath epithelial and endothelial tissues. It acts as a structural barrier, preventing cancer cells from invading and undergoing endocytosis and exocytosis. Thus, understanding the relationship between the BM and tumor immunity can lead to new strategies for halting cancer progression and metastasis. Gene expression data of 33 cancers were obtained from the Cancer Genome Atlas database. The study analyzed the correlation between BM regulatory genes, copy number variations, immune-related genes, and tumor immune dysfunction rejection (TIDE). Immunohistochemical methods were used to analyze the expression of regulatory genes. And the BM score was calculated using single-sample gene set enrichment analysis. Single-cell transcriptional sequencing determined the activation status of the BM in the tumor microenvironment. The expression of BM-related genes (BMGs) exhibited significant heterogeneity across different cancer types. Most genes were up-regulated in tumor tissues. Major single nucleotide polymorphisms of BMGs included missense mutations, while major copy number variations were heterozygous deletion and heterozygous amplification. Additionally, the expressions of immune checkpoint molecules CD276, NRP1, and C10orf54 showed positive correlations with BMS. Numerous tumors displayed a significant positive correlation between BMS and TIDE scores. We demonstrate that BM regulatory genes undergo alterations specific to different cancer types, which are associated with the expression of immune checkpoints and immune dysfunction. This indicates that BM remodeling plays an active role in modulating immune resistance, rather than being a passive structural alteration.