Cells of origin of cancers acquire the first genetic aberration(s) that lead to tumourigenesis. Identifying cells of origin in lung cancer could allow earlier detection of malignancies and more effective treatment. Stem/progenitor cells are likely tumour-initiating cells due to both their longevity, allowing for accumulation of genetic lesions, and their capacity for renewal. This study aimed to isolate lung epithelial progenitor populations to evaluate their role as the cell of origin of squamous cell carcinoma (SqCC), due to a lack of studies into the formation of this lung cancer subtype.
Cells were extracted from adjacent normal tissue of patients undergoing lung cancer resection and subjected to fluorescence-activated cell sorting (FACS). We developed a sort strategy allowing for separation of basal cells, airway cells (club, ciliated and goblet cells), and type II alveolar (AT2) cells as shown by qPCR, intracellular FACS and electron microscopy data. The basal and AT2 compartments consistently formed phenotypically distinct colonies in an in vitro assay. Linear regression analysis (>20 patients) showed a strong positive correlation between number of years of patient tobacco smoking and the colony forming capacity of the basal cells. In contrast, an inverse correlation was observed between patient smoking and proliferation of the AT2 cells.
We then used RNA sequencing to compare the genetic profiles of the lung epithelial subpopulations to different lung cancer subtypes. This comparison revealed that basal cells were more similar to SqCC than any other cancer subset, suggesting that basal cells may be the cell of origin of lung SqCC.
This study describes the isolation of two progenitor subsets from human lung and indicates a potential role for basal cells in the formation of SqCC. Future studies aim to elucidate differences between basal cells and AT2 cells that explain their distinct sensitivity to cigarette smoke exposure and how this may contribute to carcinogenesis.