BBS Faculty Member - Carla Kim

Carla Kim

Children's Hospital Stem Cell Program
Department of Genetics, Harvard Medical School

Boston Children's Hospital
Karp Building, Room 8-216
300 Longwood Ave
Boston, MA 02115
Tel: 617-919-4644
Fax: 617-730-0222
Email: carla.kim@childrens.harvard.edu
Lab Members: 4 postdoctoral fellows, 1 graduate student, 2 technicians
Visit my lab page here.



The broad interest of my lab is to characterize the biology of stem cells in the normal lung and in lung cancer using a combination of mouse genetics, cell biology and genomics approaches. Our lung stem cell studies are focused on a population of adult stem cells in murine lung, bronchioalveolar stem cells (BASCs), which we hypothesize are crucial for lung injury repair in adults. We initially showed that BASCs have the potential to differentiate into bronchiolar and alveolar lineages in two-dimensional cultures. We recently created unique three-dimensional systems that demonstrate the ability of BASCs to produce bronchiolar and alveolar structures in culture and in vivo after subcutaneous injection. We have also used genetic lineage tracing studies to demonstrate the potential of BASCs to mediate alveolar cell repair in vivo. We have developed transplant assays to deliver lung stem cells and several new mouse strains, which now allow us to track the fate of BASCs after injury or in lung disease contexts. Our new assays for studying the self-renewal and differentiation potential of lung stem cells are making it possible to address critical areas in lung biology.

Our work has identified novel molecular regulators of lung stem cells. We demonstrated that the Polycomb protein Bmi1 is required for self-renewal of BASCs, repair of lung injury, and lung tumorigenesis (Dovey et al,
PNAS). This work uncovered a much broader role for Bmi1 in adult stem cell function and tumorigenesis than was previously appreciated. More recently, we determined that p57 and a large subset of imprinted genes are Bmi1 target genes. We found that these imprinted loci are key regulators of lung stem cell self-renewal, uncovering a whole new set of stem cell regulatory genes that are likely needed in diverse adult tissue-specific stem cells (Zacharek et al, Cell Stem Cell).

My lab has also made key advances in elucidating the biology of stem cells in lung cancer. We discovered an important link between the genetic status of lung tumors and the phenotype of the tumor-propagating cells (TPCs), the cells that have the capacity to recapitulate the tumor by transplantation (often referred to as cancer stem cells). Using an orthotopic transplantation assay for TPCs that my lab created, we showed that lung cancers of different genotype have TPCs with distinct markers (Curtis et al,
Cell Stem Cell). This work identified the first bona fide lung TPC population, opening up many new opportunities to study the most crucial lung cancer cells to target for lung cancer therapy. More recently we have used our TPC assay to prospectively isolate metastatic lung cancer cells. We are currently identifying the molecular pathways crucial for metastatic TPCs.

Our current and future work will build on these discoveries to lead the field towards a better understanding of stem cell biology in the lung, development of innovative approaches for examining the cellular and molecular basis of lung disease and cancer, and identification of new avenues of therapy for pulmonary diseases.



Last Update: 7/23/2014



Publications

For a complete listing of publications click here.

 


 

Zacharek SJ, Fillmore CF*, Lau AN*, Gludish DW*, Chou A, Ho JWK, Zamponi R, Gazit R, Bock C, Jager N, Smith ZD, Kim T, Saunders AH, Wong J, Lee JH, Roach RR, Rossi DJ, Meissner A, Gimelbrant AA, Park PJ, Kim CF. (2011). Lung stem cell self-renewal relies on Bmi1-dependent control of expression at imprinted loci. Cell Stem Cell, 9(3): 272-281. PMCID: PMC3167236

Curtis SJ, Sinkevicius KW, Li D, Lau AN, Roach RR, Zamponi R, Woolfenden AE, Kirsh DG, Wong KK,
Kim CF. (2010) Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell; 7(1): 127-133. PMCID: PMC2908996.

Dovey J, Zacharek S,
Kim CF*, Lees JA*. (2008). Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proceedings of the National Academy of Sciences of the USA. 105(33):11857-11862. PMCID: PMC2575250.
*Co-corresponding authors

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.

Kim CFB, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T. (2005). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell, 121(6):823-835.



© 2014 by the President and Fellows of Harvard College