Our Research

We isolated the first stem cell population from the adult murine lung, termed bronchioalveolar stem cells (BASCs). BASCs are critically affected by an oncogenic K-ras mutation and may be the cell-of-origin of lung adenocarcinomas. We hypothesize that BASCs are the stem cells that maintain bronchiolar and alveolar cell homeostasis in vivo. We use a combination of mouse genetics, cell biology and genomics approaches to elucidate the biology of these cells during homeostasis and tumorigenesis.

Characterization of lung stem cells in vivo

One 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, it will be important to 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 and other putative lung stem cells 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 are being used as a platform to identify potential key pathways in stem cells.  Complementing gene expression studies, we are using our BASC cultures in renewing or differentiating conditions with a shRNA library to identify genes that are required to direct stem cells.  Aside from screens, analysis of candidate pathways regulating stem cells are being directly examined.

Analysis of putative lung cancer stem 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 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 tumor-propagating cells in mouse and human lung cancers.  We are also using genetic techniques 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 effect lung epithelia as well as serving to identify potential means of early detection and therapy.