Carla F. Kim, PhD
Harvard Medical School
The Kim Laboratory has pioneered the use of stem cell biology approaches for the study of adult lung progenitor cells and lung cancer. Through a combination of mouse genetics and cell biology, we have developed tools to identify and characterize cells with progenitor cell activity in adult lung tissue. We have applied our expertise in normal progenitors to the study of lung cancer, which resulted in our definition of the cancer stem cell populations in the two most common types of lung cancer. We have examined the mechanisms that regulate lung progenitor cell self-renewal and differentiation, leading to an understanding of how multiple epigenetic factors affect lung injury repair, lung tumorigenesis and response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, our research has progressed from basic biology to translational research to beginnings of clinical trials.
A major focus of the Kim Lab has been to develop tools to characterize progenitor cells in the adult lung; our contributions have helped bring lung biology to the forefront of stem cell biology. We have investigated the in vivo capacity of lung progenitors using genetic lineage tracing, which demonstrated the potential of lung epithelial cells expressing the bronchiolar cell marker CCSP to mediate alveolar cell repair in vivo (Tropea et al, AJP Lung 2012). We expanded our approach to create three-dimensional co-culture and co-transplantation organoid systems that have begun to define the cell-cell crosstalk between epithelial progenitors, endothelial cells and mesenchymal cells in the lung. We can now visualize the formation of airway- and alveolar-like structures from single cells, and we have a way to precisely define how differentiation is controlled at the molecular level. For example, we showed that lung epithelial progenitors and lung endothelial cells interact in a novel BMP4-NFATc1-TSP1 signaling axis that drives lineage-specific differentiation (Lee et al, Cell 2014). We have recently used our organoid system to define lung mesenchymal cell types that specifically regulate airway or alveolar epithelial cells (Lee et al, Cell, 2017). It is now possible with our system to assess the function of diverse lung epithelial progenitor cells and their mesenchymal and endothelial partners.
Until now, systems have not been available to understand which, if any, lung diseases are a result of failure of lung progenitor cell activity or altered cell-cell interactions between epithelial progenitors and their regulatory stromal cells. The tools we developed make it possible to understand the cell autonomous and the paracrine mechanisms of lung progenitor cell biology that may be altered in pulmonary disease. In projects supported by two different R01s, we are exploring how BMP4-NFATc1-TSP1 signaling affects alveolar differentiation in mouse models of pulmonary fibrosis and the premature infant lung disease bronchopulmonary dysplasia, respectively. We are also applying organoid techniques to study the impact of modifier gene mutations in lung epithelial cells derived from cystic fibrosis patients’ induced pluripotent stem cells.
The Kim Lab has made key advances in elucidating the biology of stem cells in lung cancer. We used genetically engineered mouse models that accurately represent human lung cancer and created an orthotopic transplantation assay to successfully propagate tumors in recipient mice. Using this assay, we identified cancer stem cell populations in the two most frequent types of lung cancer (Curtis et al, Cell Stem Cell 2010 and Xu and Fillmore et al, Cancer Cell 2014) and we showed that cancer stem cells contribute to metastatic lung cancer (Lau et al, EMBO, 2014). We discovered an important link between the genetic status of tumors and the phenotype of the cancer stem cells; the tumor propagating cells (TPCs) from three genetically distinct mouse models of lung cancer had distinct markers (Curtis et al, Cell Stem Cell 2010). We showed how various epigenetic mechanisms influence lung epithelial progenitor cells and lung cancer (Dovey et al, PNAS 2008; Zacharek et al, Cell Stem Cell 2011). Our expertise in epigenetics led us to experiments that revealed a new combination therapy approach for particular subsets of lung cancer patients (Fillmore et al, Nature 2015). Because of our work, companies are now performing pre-clinical studies combining EZH2 inhibitors with chemotherapeutic agents for lung cancer.