Abstract
Lung cancer and chronic lung diseases impose major disease burdens worldwide and are caused by inhaled noxious agents including tobacco smoke. The cellular origins of environmental-induced lung tumors and of the dysfunctional airway and alveolar epithelial turnover observed with chronic lung diseases are unknown. To address this, we combined mouse models of genetic labeling and ablation of airway (club) and alveolar cells with exposure to environmental noxious and carcinogenic agents. Club cells are shown to survive KRAS mutations and to form lung tumors after tobacco carcinogen exposure. Increasing numbers of club cells are found in the alveoli with aging and after lung injury, but go undetected since they express alveolar proteins. Ablation of club cells prevents chemical lung tumors and causes alveolar destruction in adult mice. Hence club cells are important in alveolar maintenance and carcinogenesis and may be a therapeutic target against premalignancy and chronic lung disease.
Highlights
Chronic lung diseases present tremendous health burdens attributed to dysfunctional alveolar repair [1]
Co-localization of mG+ labeling with lineage marker proteins revealed complete mG+ labeling of all airway epithelial cells (AEC) but not of alveolar cells in membranous tdTomato (mT)/mG;Scgb1a1.Cre mice, of most AEC and all alveolar type II cells (ATII) cells in mT/mG;Sftpc.Cre mice, and of some ATII cells and all alveolar macrophages in mT/mG;Lyz2.Cre mice (Figure 1A and Figures S1B and S1C)
Lung flow cytometry of six-week-old mT/mG;Scgb1a1.Cre, mT/mG;Sftpc.Cre, and mT/mG;Lyz2.Cre mice estimated the proportions of mG+ marked cells in concordance to microscopy (Figure 1A and Figures S1A and S1D)
Summary
Chronic lung diseases present tremendous health burdens attributed to dysfunctional alveolar repair [1]. The identification of the cellular and transcriptomic events that underlie lung regeneration and carcinogenesis is extremely important, since epithelial developmental pathways are intimately related with oncogenic signaling to jointly regulating stemness and drug resistance [5, 6]. To this end, lineage-specific genes encoding epithelial proteins that support the physiological functions of the lungs were recently shown to suffer non-coding insertions and deletions in LUAD, lending further support to the longstanding notion that epithelial cells that express lung-restricted proteins are the cellular sources of LUAD [7]. The mutational landscape of human LUAD is closely mirrored by tobacco carcinogen-induced, but not by oncogenic KRAS-driven mouse lung tumors [15]
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