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

RATIONALE: During tumorigenesis, approximately 20% of EGFR-mutant 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 to 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, 3-D 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 progenitor FOXD1. Therapeutic hyperoxia (60% O2) restored lineage balance and attenuated tumorigenesis. CONCLUSIONS: A pre-existing hypoxic niche is a key spatial determinant of early malignant progression in EGFR-mutant LUAD, engaging ribosome-collision signaling through the ZAKα-MAPK-c-Fos axis and promoting alveolar lineage disruption. Restoring oxygenation, either through controlled hyperoxia or pharmacologic inhibition of this pathway, may help curb tumorigenesis and rapid progression of centrally located lesions.