An endothelial-centered regulatory framework reveals context-dependent roles of MYLK in lung adenocarcinoma

作者：Rui Li, Xi Liu, Chen Huo, Jian-Ping Li, Yuxin Zhang, Shuang-Teng Liu, Yi Qu · 发表于：Frontiers in Immunology · 年份：2026 · DOI：10.3389/fimmu.2026.1719296 · 被引用次数：1 · 研究领域：Angiogenesis and VEGF in Cancer、Caveolin-1 and cellular processes、Hippo pathway signaling and YAP/TAZ

Background: Lung adenocarcinoma (LUAD) is shaped by the tumor microenvironment, yet endothelial cell (EC) regulatory programs and their biological roles remain insufficiently defined. Methods: We analyzed scRNA-seq data to map EC-associated programs and applied hdWGCNA to identify EC modules and communication patterns. Network pharmacology integrated EC-module genes with LUAD-related targets to prioritize MYLK. MYLK expression and function were evaluated by RT-qPCR, immunohistochemistry, and gain-/loss-of-function assays in endothelial and LUAD cell models. We then performed network-based in silico knockout in LUAD tumors (GSE164789) and exploratory immune-cell eQTL analysis. Results: EC modules were enriched for junction organization, angiogenesis, and immune-related pathways, with extensive epithelial-stromal-endothelial interactions. Network pharmacology nominated MYLK as an EC-linked LUAD candidate. MYLK expression was reduced in LUAD and associated with unfavorable clinical outcomes. In endothelial cells, MYLK perturbation altered junction integrity and trans-endothelial tumor cell migration; in LUAD cells, MYLK gain/loss affected migration, invasion, and proliferation. In silico knockout of MYLK produced regulatory shifts enriched for tight junction organization, endothelial apoptosis, angiogenesis, vascular permeability, and vascular/cancer-related pathways. Immune-cell eQTL analysis identified an association between increased MYLK expression in dendritic cells and ele...