Characterization of Lung Stem Cells in vivo:
The current experimental focus of our lab is to test the potential of BASCs in vivo. Expanding on work showing that BASCs are multipotent in culture, we will determine the potential of isolated BASCs to produce lung epithelial cells in animal models. However, lack of functional tests for lung stem cells precludes understanding the role of BASCs in the mechanisms of lung disease as well as their potential beneficial uses. Therefore, we are developing transplantation methods to determine if isolated BASCs can give rise to bronchiolar and alveolar cells in vivo.
Complementing a transplantation assay, lineage tracing will be performed to assess the potency of BASCs without removing them from the lung. We are currently creating the knock-in mice and other tools necessary to perform lineage tracing in the adult lung in vivo. Finally, we are also using preclinical models of lung injury and lung cancer to elucidate how lung disease impacts lung stem cell function.
Elucidation of Molecular Mechanisms Controlling Stem Cells:
BASCs provide a tool with which to define the mechanisms that control epithelial stem cell self-renewal and lineage-specific differentiation. Expression profiles of BASCs from normal, injured and tumorigenic lung will be used as a platform to identify potential key pathways in stem cells. Complementing gene expression studies, BASC cultures will be placed under renewing or differentiating conditions with a small hairpin RNA library to identify genes that are required to direct stem cells. Aside from screens, we are directly examining the analysis of candidate pathways regulating stem cells.
Analysis of lung tumor-propogating cells:
Recent work in other solid tumors indicates that only a small fraction of the cells within a tumor are required for tumor growth in transplantation assays. These rare cancer cells have been named cancer stem cells, and it is hypothesized that cancer stem cells are resistant to chemotherapeutic agents. In order to cure cancer, it may be crucial to develop treatments that specifically eliminate cancer stem cells. However, it is not known if lung tumors contain cancer stem cells.
We have established a transplantation assay to compare the ability of murine lung cancer cell populations to propagate lung cancer in recipient immunocompromised mice. We are using currently defined BASC markers and markers of cancer stem cells from other tissues to identify a cancer stem cell population in murine lung cancers. We are also using genetic techniques to identify lung cancer stem cells and to understand the heterogeneity of cancer cells.
Our work will provide the foundation required for innovative approaches to examine the cellular and molecular basis of cancer and other diseases that affect lung epithelia as well as serving to identify potential means of early detection and therapies.