Identifying Epithelial-Cell Progression Signatures (ECPSs) from Multi-Resolution Multi-Omics Data for Translational Clinical Applications in Lung Adenocarcinoma

作者：Xueyao Chen, Tongxin Lv, Yang Wu, Fangfang Fan, Shaobo Kang, Renjie Dou, Wanmei Zhang, Dongxue Li, Rui Li, Yanyan Ping · 发表于：International Journal of Molecular Sciences · 年份：2026 · DOI：10.3390/ijms27156819 · 研究领域：Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers、Lung Cancer Treatments and Mutations

Dynamic transcriptomic remodeling of epithelial cells represents a critical hallmark of lung adenocarcinoma (LUAD) progression, yet epithelial-cell progression signatures (ECPSs) linked to this process remain incompletely characterized, impeding our understanding of malignant LUAD transformation. Here, we performed a multi-resolution multi-omics study and identified two functionally opposing ECPSs: a Cancer-Promoting Signature (CPS) and a Cancer-Suppressing Signature (CSS). The CPS was progressively upregulated from normal to early- and advanced-stage lesions, while the CSS was gradually downregulated, and both were validated by multi-resolution transcriptomic data. Both the CPS and CSS demonstrated robust diagnostic value for LUAD, particularly in early-stage detection (median AUC > 0.95). In seven independent validation cohorts, the CPS and CSS served as robust prognostic risk and protective factors, respectively. Their combination could better stratify LUAD patients into distinct prognostic subgroups, with the CPShigh–CSSlow subgroup showing the worst prognosis, accompanied by high genomic instability, an immunosuppressive tumor microenvironment, and resistance to chemotherapy. Notably, the CPS and CSS exhibited broad translational value in other epithelium-derived cancers. HMGA1, a key CPS gene, showed epithelium- and advanced-stage-specific high expression, which was significantly associated with poor prognosis, genomic instability, and immune escape. Collectively, ou...