Hypoxic niche drives lineage imbalance and early tumorigenesis in EGFR -mutant lung cancer

作者：Fanchen Meng, Zhijun Xia, Siwei Wang, Qian Wang, Meng Zhu, Jing You, Qinglin Wang, Ziyang Shen, Qinhong Sun, J. Li, Zhitong Li, Pengcheng Zhu, Yuxiang Sun, Jie Wang, Qianghu Wang, Hongxia Ma, TongYan LIU, Lin Xu, R. Yin · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2026 · DOI：10.1093/ajrccm/aamag150 · 被引用次数：1 · 研究领域：Single-cell and spatial transcriptomics、Cancer, Hypoxia, and Metabolism、Ferroptosis and cancer prognosis

RATIONALE: During tumorigenesis, approximately 20% of EGFR-mutant lung adenocarcinomas (LUADs) progress rapidly to aggressive subtypes. Multi-omics analyses of stage I LUAD cohorts have revealed that centrally located lesions exhibit enhanced tumorigenic potential compared with peripheral counterparts, whereas the underlying mechanisms remain elusive. OBJECTIVES: To define the spatial-clinical determinants of early aggressive progression in EGFR-mutant LUAD and develop a lineage-based mechanistic framework connecting regional microenvironmental constraints with epithelial cell-state remodeling and invasive acquisition. METHODS: We conducted an integrated multi-omics analysis combining clinical cohort data (n = 277), single-cell and spatial transcriptomics, and functional studies in genetically engineered mouse models to identify spatial-clinical patterns. Mechanistic studies were carried out using mouse models, 3D organoids, and controlled oxygen interventions to investigate the effects of hypoxia on cellular transformation. MEASUREMENTS AND MAIN RESULTS: Our analysis revealed that centrally located lesions display enhanced tumorigenic potential compared to peripheral counterparts, driven by hypoxic niche. Hypoxic preconditioning (10% O2) induced ribosome collisions in EGFR-driven mouse models and organoids, activating the ZAKα-MAPK-c-Fos axis to disrupt alveolar lineage imbalance, characterizing as suppressing alveolar epithelial factor NKX2-1 while elevating stem-like proge...