Understanding the Mechanisms of Smoking Induced Squamous Lung Cancer

Premalignant lesions occur in the proximal airway epithelium after smoking injury and are thought to undergo stepwise progression from low-grade to high-grade lesions and ultimately to invasive squamous lung cancer (SLC). However, premalignancy of the airway is poorly understood; most of these premalignant lesions will resolve, and the mechanisms of premalignant lesion formation and resolution are not known. It is also not known which lesions will go on to progress to SLC and how this process occurs. A novel approach to cure patients of lung cancer is to develop a targeted chemoprevention strategy to prevent the formation of premalignant lesions and therefore SLC in the first place. This approach requires a good understanding of the biology of airway premalignant lesions and stepwise progression to SLC. Understanding the gene expression changes within cell populations in the airway, premalignant lesions and SLC will allow us to understand how stepwise progression occurs. We hypothesize that the gene expression profiles of individual cells undergoing transformation to SLC will allow us to understand the cell of origin for premalignant lesions and SLC and the mechanisms involved in stepwise progression to SLC. Understanding this process will allow us to prevent the excessive proliferation of premalignancy and impact the lung cancer field by developing a novel chemoprevention strategy for SLC. We propose to achieve our goal with the following Specific Aims: Specific Aim 1: To identify gene expression profiles of single cells in normal human airway epithelium and SLC cell lines to determine heterogeneity of these cell populations and find common signatures that could be associated with lung carcinogenesis. Specific Aim 2: to perform high throughput single cell sequencing of histologically normal airway epithelium, premalignant lesions and SLC from patients. We will characterize the heterogeneity between subpopulations of cells that associate with the presence of lung cancer.