|
|
 |
|
|
The Kim Lab
|
|
|
|
| Carla Kim is a Principal Investigator at Children's Hospital Boston and an Assistant Professor in the Department of Genetics at the Harvard Medical School. |
Dr. Carla Kim is interested in the relationships between stem cell biology, cancer biology, and lung biology. Carla earned her doctorate in Genetics at the University of Wisconsin, Madison. As a graduate student in the laboratory of John Petrini, she 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 suseptibility 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.
|
|
|
|
|
|
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 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 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 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 effect lung epithelia as well as serving to identify potential means of early detection and therapy.
|
|
|
|
|
Rebecca Roach, Research Assistant II
Sima Zacharek, Ph.D., Postdoctoral Fellow
Stephen Curtis, Graduate student
David Raiser, Graduate student
Alan Chou, Undergraduate student
|
|
|
|
|
* 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.
* Kim, CFB, Jackson EL, Kirsch DG, Grimm J, Shaw AT, Lane K, Kissil J, Olive KP, Sweet-Cordero A, Weissleder, Jacks T. Mouse models of human non-small-cell lung cancer: raising the bar. Cold Spring Harbor Symposia on Quantitative Biology, 2005, Volume LXX:241-250.
* Kim, CFB. Advancing the field of lung stem cell biology. Frontiers in Bioscience 2007;12:3117-3124.
*Kim CF. Paving the road for lung stem cell biology: bronchioalveolar stem cells and other putative distal lung stem cells. Am J Physiol Lung Cell Mol Physiol. 2007 Nov;293(5):L1092-8. Epub 2007 Aug 10.
|
|
|
|
|
|
|
