Genetic mutation and dysfunction of AT2 cells drive B(a)P/LPS-induced inflammation-related lung tumorigenesis: evidence and mechanism of autophagy.

The environmental pollutant benzo(a)pyrene (B(a)P), a representative polycyclic aromatic hydrocarbon (PAH), is a recognized carcinogen, and chronic pulmonary inflammation is closely associated with lung carcinogenesis. Although alveolar type 2 (AT2) cells are the origin of lung adenocarcinoma, the genetic and functional changes in AT2 cells and the mechanisms involved in inflammation-related lung tumorigenesis have not been elucidated. Here, C57BL/6J mice are exposed to B(a)P and the inflammatory irritant lipopolysaccharide (LPS) to establish a model of inflammation-related lung tumorigenesis. Single-cell RNA sequencing is performed on lung tissues. DNA mutations in AT2 cells are analyzed via whole-exome sequencing. The protein expression of AT2 cells in lung cancer tissue is determined by immunofluorescence staining. The results reveal that LPS promotes B(a)P-induced lung tumorigenesis; in the whole lungs of B(a)P/LPS, a decreased proportion, altered differentiation trajectory, and increased gene mutation number in AT2 cells are observed. Additionally, in B(a)P/LPS-treated lung cancer tissue, the levels of γ-H2AX DNA damage and the proliferation marker Ki67 in AT2 cells are increased, whereas the levels of differentiation markers are decreased. Single-cell RNA transcriptomics reveals that the autophagy-related genes Foxo3 and Ppp2r5, which are enriched in the PI3K-Akt pathway, and the autophagy-related genes in AT2 cells in lung cancer are decreased in the B(a)P/LPS group. Thus, chronic inflammation promotes DNA damage, gene mutation and dysfunction in AT2 cells, and decreased autophagy in AT2 cells may be an important mechanism for inflammation-related lung tumorigenesis.