Cancer-prone Phenotypes and Gene Expression Heterogeneity at Single-cell Resolution in Cigarette-smoking Lungs

Single-cell RNA sequencing (scRNA-seq) technologies have been broadly utilized to reveal molecular mechanisms of respiratory pathology and physiology at single-cell resolution. Here, we established single-cell meta-analysis (scMeta-analysis) by integrating data from eight public datasets, including 104 lung scRNA-seq samples with clinicopathologic information and designated a cigarette-smoking lung atlas. The atlas revealed early carcinogenesis events and defined the alterations of single-cell transcriptomics, cell population, and fundamental properties of biological pathways induced by smoking. In addition, we developed two novel scMeta-analysis methods: VARIED (Visualized Algorithms of Relationships In Expressional Diversity) and AGED (Aging-related Gene Expressional Differences). VARIED analysis revealed expressional diversity associated with smoking carcinogenesis. AGED analysis revealed differences in gene expression related to both aging and smoking status. The scMeta-analysis paves the way to utilize publicly-available scRNA-seq data and provide new insights into the effects of smoking and into cellular diversity in human lungs, at single-cell resolution. SIGNIFICANCE: The atlas revealed early carcinogenesis events and defined the alterations of single-cell transcriptomics, cell population, and fundamental properties of biological pathways induced by smoking.