PT  - JOURNAL ARTICLE
AU  - Magda Spella
AU  - Ioannis Lilis
AU  - Mario A. Pepe
AU  - Yuanyuan Chen
AU  - Maria Armaka
AU  - Anne-Sophie Lamort
AU  - Dimitra E. Zazara
AU  - Fani Roumelioti
AU  - Malamati Vreka
AU  - Nikolaos I. Kanellakis
AU  - Darcy E. Wagner
AU  - Anastasios D. Giannou
AU  - Vasileios Armenis
AU  - Kristina A.M. Arendt
AU  - Laura V. Klotz
AU  - Dimitrios Toumpanakis
AU  - Vassiliki Karavana
AU  - Spyros G. Zakynthinos
AU  - Ioanna Giopanou
AU  - Antonia Marazioti
AU  - Vassilis Aidinis
AU  - Rocio Sotillo
AU  - Georgios T. Stathopoulos
TI  - Dual airway and alveolar contributions to adult lung homeostasis and carcinogenesis
AID  - 10.1101/531780
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 531780
4099  - http://biorxiv.org/content/early/2019/01/27/531780.short
4100  - http://biorxiv.org/content/early/2019/01/27/531780.full
AB  - Lung adenocarcinoma (LUAD) and chronic lung diseases caused by smoking and environmental noxious agents are the deadliest diseases worldwide, sharing a partially charted pathobiology of dysfunctional alveolar repair. Here we sought to identify the respiratory epithelial dynamics and molecular signatures participating in adult lung maintenance and chemical carcinogenesis. We employed novel mouse models of respiratory epithelial marking and ablation, a battery of pulmonary toxins and carcinogens, experimental protocols of carcinogen-induced LUAD, tobacco carcinogen-induced LUAD cell lines, and human transcriptomic data and identified a prominent involvement of airway molecular programs in alveolar maintenance and carcinogen-induced LUAD. The airway-specific transcriptomic signature was redistributed to the alveoli after toxic and carcinogenic insults and resulted in marked contributions of airway-labeled cells to injury-recovered alveoli and LUAD. Airway cells maintained Kras mutations and therefore possibly contributed to lung cancer initiation, while LUAD were spatially linked to neighboring airways. Transcriptomic profiling of carcinogen-induced murine and human LUAD revealed enrichment in airway signatures, while ablation of airway cells distorted alveolar structure and function and protected mice from LUAD development. Collectively, these results indicate that airway cells and/or transcriptomic signatures are essential for alveolar maintenance and LUAD development.