Carla Bender Kim
Children's Hospital Stem Cell Program
Department of Genetics, Harvard Medical School
Harvard Stem Cell Institute
300 Longwood Ave., Karp Building, Room 8-216
Boston, MA 02115
4 postdoctoral fellows, 2 graduate students, 1 lab manager
The broad interest of our lab is to characterize the biology of stem cells in normal tissue and in disease. We developed a method to isolate 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 use a combination of mouse genetics, cell biology and genomics approaches to elucidate the biology of BASCs and other lung cells during homeostasis and tumorigenesis. An understanding of stem cell functions and regulation in normal lung will be important for innovative approaches to examine the cellular and molecular basis of cancer and diseases that effect lung epithelia as well as serving to identify potential means of early detection and therapy.
Characterization of lung stem cells in vivo
One current experimental focus of our lab is to test the potential of BASCs in vivo. We are developing transplantation methods to determine if isolated BASCs can give rise to bronchiolar and alveolar cells in vivo. We are also creating the knock-in mice and other tools necessary to perform lineage tracing to assess the potency of BASCs without removing them from the lung.
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, BASC cultures are 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.
- Curtis SJ, Sinkevicius KW, Li D, Lau AN, Roach RR, Zamponi R, Woolfenden AE, Kirsh DG, Wong KK, Kim CF. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell, 2010; 7: 127-133.
- 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. *co-corresponding authors
- Nolen-Walston RD*, Kim CF*, Mazan MR, Ingenito EP, Gruntman AM, Tsai L, Boston R, Woolfenden AE, Jacks T, Hoffman AM. Cellular kinetics and modeling of bronchioalveolar stem cell response during lung regeneration. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2008; 294:L1158-L1165. *equal contribution
- 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.
- 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 Harb Symp Quant Biol 2008. 73: 479-490.
BBS webpage updated 5/11/2010