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.

上皮癌细胞需要穿透基底膜（basement membrane, BM）才能发生转移。基底膜是上皮组织与内皮组织下方的薄层细胞外基质，作为结构性屏障阻止癌细胞侵袭，并阻断胞吞与胞吐过程。因此，阐明基底膜与肿瘤免疫的关联，可为阻断癌症进展与转移提供全新策略。本研究从癌症基因组图谱（Cancer Genome Atlas）数据库获取了33种癌症的基因表达数据，分析了基底膜调控基因、拷贝数变异、免疫相关基因与肿瘤免疫功能异常和排斥（tumor immune dysfunction rejection, TIDE）之间的相关性。采用免疫组化方法分析调控基因的表达水平，并通过单样本基因集富集分析计算基底膜评分。借助单细胞转录组测序明确了肿瘤微环境中基底膜的激活状态。基底膜相关基因（BM-related genes, BMGs）的表达在不同癌症类型中呈现显著异质性，多数基因在肿瘤组织中呈上调表达。基底膜相关基因的主要单核苷酸多态性类型为错义突变，主要拷贝数变异类型为杂合缺失与杂合扩增。此外，免疫检查点分子CD276、NRP1与C10orf54的表达与基底膜评分呈显著正相关，多数肿瘤的基底膜评分与TIDE评分亦呈现显著正相关。本研究证实，基底膜调控基因存在癌症类型特异性的改变，且该改变与免疫检查点表达及免疫功能异常相关，提示基底膜重塑在调控免疫抵抗中发挥主动作用，而非仅为被动的结构性变化。