Air pollutants remodel mutant epithelia toward a convergent lung adenocarcinoma progenitor state

The lung epithelium harbours progenitor populations, including basal, club, neuroendocrine, and alveolar type I/II (AT1/AT2) cells. A highly plastic Krt8+ alveolar intermediate cell state (KAC) arises in Kras -driven tumorigenesis and in lung injury models. Environmental particulate matter (PM) exposure promotes lung tumorigenesis through macrophage-derived interleukin-1beta (IL-1beta). How EGFR mutations (EGFRm), the most common genomic driver of lung cancer in never-smokers, and tumour promotion drive lung adenocarcinoma (LUAD) at the single cell level from diverse lung epithelial lineages remains unclear. Understanding this will aid development of molecularly targeted prevention approaches, particularly in never-smokers. We generated mouse models of lineage-specific activation of EGFR-L858R within basal, club, neuroendocrine, and AT2 lineages. LUAD development and lineage convergence were assessed using histology and snRNA-seq across 37,627 cells from 100 mice. For PM effects, EGFR-L858R induction in AT2 cells was achieved via Ad5-Spc-Cre intratracheal instillation, followed by PM or PBS exposure. 10X multiome snRNA-seq (34,459 AT2-lineage cells) and snATAC-seq were used to profile transcriptional and epigenetic changes. EGFRm precision-cut lung slices (PCLS) were exposed to PM ex vivo in presence of IgG or anti- IL-1beta blocking antibodies. Our analysis revealed that LUAD arises from basal, club, neuroendocrine, and AT2 lineages - all converging on an alveolar-like state, mirroring the trajectory observed in KRAS-driven LUAD. Notably, alveolar KACs were detected in EGFRm cells derived from basal, club, and AT2 lineages, indicating a conserved transitional state during early tumorigenesis. EGFRm activation also induced KAC-signature genes while preserving lineage-specific markers, reflecting a dual programme of lineage convergence and memory. Upon PM exposure, EGFRm KACs exhibited pronounced upregulation of stress-responsive and inflammation-induced epithelial genes. Compared with wild-type AT2 controls, PM-exposed EGFRm KACs exhibited strong enrichment of LUAD-associated transcripts, with over 30% overlap encompassing 1,298 genes. This highlights the synergy between EGFRm and environment-induced injury. Furthermore, we identified epigenetic rewiring of KACs, marked by activation of transcription factors linked to the IL-1beta pathway upon PM. Functionally, blocking IL-1beta in PCLS effectively inhibited KAC formation, establishing a mechanistic link between inflammatory signalling and early tumour cell fate. In conclusion, we showed that epithelial lineages converge on KACs en-route to EGFR -driven LUAD, which expands and undergoes transcriptional and epigenetic remodelling upon PM-exposure. Future studies defining key regulators of KAC expansion and its IL-1beta dependency could inform novel therapeutic avenues for molecular cancer prevention.