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 c