Identification of a Conserved Dedifferentiated Cancer Cell State Stratifying Poor Survival in Lung Adenocarcinoma

Abstract Cancer cell plasticity underlies therapeutic resistance, yet its determinants remain poorly understood. While genetic mutations drive carcinogenesis, the non-malignant cell-of-origin state also dictates tumor behavior. Using single-cell transcriptomics, we characterized cancer cell subpopulations in lung adenocarcinoma by integrating non-malignant alveolar type 2 and cancer cell transcriptional states. In clinical trial bulk transcriptomes, gene signatures of four malignant subpopulations (Groups 0–3) revealed that Group 1 is strongly associated with significantly worse overall survival and exhibits a highly aggressive phenotype with stemness, hypoxia, epithelial-mesenchymal transition and intermicrovillar adhesion complex dysregulation. An ElasticNet Cox model trained on pooled cohorts (IMpower150 + OAK, N = 1,572, events = 1,205) yielded a 35-gene risk signature. In locked-model validation across held-out cohorts (IMpower110, IMpower130, BIRCH, and POPLAR), high Group 1 risk scores demonstrated strong prognostic value for elevated mortality (pooled random-effects hazard ratio [HR] = 1.326 per 1 SD increase, 95% CI: 1.218 to 1.443; p < 0.001), and tertile contrast confirmed pronounced survival separation (HR = 1.971, 95% CI: 1.486 to 2.614). In multivariable Cox regression, the signature was independent of age, sex, treatment regimen, smoking status and geographic location. High-risk patients across immunotherapy and chemotherapy exhibited strong activation of pro-survival and oncogenic networks (e.g., EGFR, PI3K and MAPK), whereas low-risk patients showed higher immune-related pathway activity (e.g., JAK-STAT). These findings suggest that cancer cells co-opt conserved developmental programs associated with poor outcomes regardless of treatment. The 35-gene Group 1 signature is a robust prognostic biomarker across immunotherapy and chemotherapy and provides a foundation for rational combination strategies.