Dual airway and alveolar contributions to adult lung homeostasis and carcinogenesis

Abstract

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 injuryrecovered 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.

Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer

“…Selective ablation of bronchiolar epithelial cells results in the loss of circadian clock oscillations in mouse lung slices, demonstrating that airway epithelial cells are key circadian oscillators within the lung (12). NSCLC is a cancer of epithelial origin (13,14), so this reinforces the hypothesis that disruption of the circadian machinery could trigger harmful events due to dysregulation of homeostasis, resulting in increased risk of lung tumor development.…”

Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy

“…[1][2][3] Lung adenocarcinoma has been postulated to originate from club cells, AT2 cells, or BASCs, while squamous cell carcinomas likely arise from basal cells. [4][5][6] Experimental models have shown that given different oncogenes, lung cells can be more or less "fit" to form fully malignant lesions. [7][8][9] However, the cellular origins for the majority of lung cancers have not been clarified yet.…”

Mutual regulation of transcriptomes between pneumocytes and fibroblasts mediates alveolar regeneration

“…Mouse studies suggest that club cells located at the terminal bronchioles serve as progenitor cells not only for airway cells but also for AT2like cells and are likely involved in regeneration of the lung after severe injury. Whether these club cells, which express AT2 markers, actually differentiate into true AT2 cells, or whether they have other, unknown functions in the regeneration and repair of the lung parenchyma after severe damage, is not completely understood [5][6][7][8][9]. Single cell analysis revealed that the human respiratory bronchioles also contain secretory airway epithelial cells that are able to differentiate into AT2 cells [10].…”