Abstract

Our long-term goal is to elucidate the role of stem cells in lung homeostasis as a prerequisite to the development of therapeutic strategies that can be used to prevent or attenuate lung disease and lung cancer. Our previous experience isolating the first stem cell population from the adult murine lung, termed bronchioalveolar stem cells (BASCs), and our demonstration of a role for these cells in lung cancer, serves as a platform to address these questions. We have recently developed three-dimensional co-culture and subcutaneous co-injection assays that allow us to quantitatively assess the identity and the differentiation potential of lung stem cells. This approach led us to uncover a cross-talk between lung endothelial cells and lung stem cells via a novel signalling axis involving Bmp4, NFATc1 and Tsp1; this pathway drives BASCs to differentiate into the alveolar epithelial cell lineage. Our work in the intersection of stem cell biology and lung disease has expanded into new insights for understanding metastasis and non-small cell lung cancer (NSCLC). We previously showed the adenocarcinoma Kras/p53 mutant mouse model contains Sca1+ tumour-propagating cells (TPCs), the cells that recapitulate the tumour by transplantation. We recently showed multiple lung tumour sub-populations can give rise to metastatic disease, and that the Sca1+ CD24+ TPCs have the highest metastatic potential. We also showed the Hippo pathway mediators Yap/Taz are necessary and sufficient for lung cancer progression. Finally, in a new mouse model of lung squamous cancer, the second most common type of NSCLC, we identified a TPC population defined by the markers Sca1 and NGFR. These studies illustrate the utility of stem cell biology approaches to provide new avenues for lung cancer therapeutic targeting.