Airway cells in adult lung homeostasis and carcinogenesis

Background: Respiratory epithelial dynamics and molecular signatures participating in adult lung maintenance and chemical carcinogenesis need to be clearly identified. Aims: We used mouse models of lung epithelial fate to chart the contribution of the respective cell lineages in the mouse lung during aging and after challenge with noxious and carcinogenic insults. Methods: We generated lung cell fate reporter mice by crossing Scgb1a1.Cre, Sftpc.Cre and Lyz2.Cre mice with the mT/mG Cre-reporter mice, resulting in expression of GFP in all Cre-recombined cells. These reporter mice were then subjected to various noxious (bleomycin and naphthalene administration at 0.08 units and 250 mg/kg, respectively; n≥10 mice/group) and carcinogenic insults (urethane administration at 1 g/Kg; n≥10 mice/group). The GFP-labelled cells were then monitored in the injured lungs and the developed adenocarcinomas. Results: We observed that lung adenocarcinomas were spatially linked to neighboring airways. The cells of all tumors of GFP;Sftpc.Cre mice and all cells of ~50% of GFP;Lyz2.Cre tumors were GFP+. Interestingly, a significant cell proportion of all tumors of GFP;Scgb1a1.Cre mice were GFP+, indicating a bronchial origin. Furthermore, the airway-specific signature was redistributed to the alveoli after toxic insults and resulted in marked contributions of airway-labeled cells to injury-recovered alveoli. Our results also indicate that airway cells maintain Kras mutations, possibly contributing to lung cancer initiation. Conclusions: Our findings identify an involvement of airway molecular programs in alveolar maintenance and carcinogen-induced lung adenocarcinomas. Funding General Secretariat for Research and Technology (GSRT) and Hellenic Foundation for Research and Innovation (HFRI) grant #1853.