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

Abstract 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.