Watch a video about lung cancer research in the Kim Lab here.
Carla earned her doctorate in Genetics at the University of Wisconsin, Madison. As a graduate student in the laboratory of John Petrini, she had studied the role of the Rad50 gene in DNA damage responses and homeostasis in vivo. She found that a point mutation in the murine Rad50 gene led to bone marrow failure (likely due to hematopoietic stem cell failure) as well as increased susceptibility to hematopoietic malignancy.
These studies stimulated her interest in determining if stem cells played a role in the initiation of cancer. She went on to a postdoctoral position in the laboratory of Tyler Jacks at the Massachusetts Institute of Technology Center for Cancer Research. There she developed a method to isolate the first stem cell population from the adult murine lung, termed bronchioalveolar stem cells (BASCs). She also showed that BASCs are critically affected by an oncogenic K-ras mutation and may be the cell-of-origin of lung adenocarcinomas. Carla Kim joined the Stem Cell Program at Children’s Hospital Boston and established her laboratory in September 2006.
The broad interest of the Kim Lab is to characterize the biology of stem cells in normal lung and lung cancer. Numerous lung diseases such as cystic fibrosis or chronic obstructive pulmonary disease involve injured or depleted bronchiolar or alveolar epithelium. Bronchiolar and alveolar cells are also affected in adenocarcinoma, the most common form of lung cancer. It is likely that lung stem cells are critically affected in patients with these devastating diseases.
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. We use a combination of mouse genetics, cell biology, and genomics approaches to elucidate the biology of lung stem cells during homeostasis and tumorigenesis. For more information, go to http://kim.tchlab.org/
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 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 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.
Dovey J, Zacharek S, Kim CF*, Lees JA*. Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc. Natl. Acad. Sc. 2008; 105:11857-11862.
Raiser DM, Zacharek SJ, Roach RR, Curtis SJ, Sinkevicius KW, Gludish DW, Kim CF. Stem cell biology in the lung and lung cancers: employing pulmonary context and classic approaches. Cold Spring Harbor Symposium on Control and Regulation of Stem Cells, 2008 Nov 26 [Epub ahead of print].
Kim, CFB. Advancing the field of lung stem cell biology. Frontiers in Bioscience 2007;12:3117-3124.
Kim CFB, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005;121:823-35.
For further information on the Kim Lab, please go to http://kim.tchlab.org/