- Normal and Leukemic Stem Cells – Characterization and Regulation
- Normal and Malignant Breast Stem Cells – Characterization and Regulation
- Derivation of Hematopoietic Cells from Human Embryonic and Induced Pluripotent Stem Cells
Experiments in this laboratory and elsewhere have established the existence in adults (both mouse and man) of primitive hematopoietic stem cells capable of permanently reconstituting the production of mature blood cells in marrow-ablated or suppressed recipients. A major part of our work continues to focus on the development, validation and use of quantitative assays that are specific for biologically distinct subsets of these stem cells using syngeneic (mouse-mouse) and xenogeneic (human-mouse) hosts. From large sets of in vitro and in vivo experiments of clonally monitored responses of individual highly purified stem cells, we have recently discovered two sources of their heterogeneous behaviour. One is determined by the complement of externally-derived signals to which the stem cells are exposed. The second appears to be intrinsically determined leading to a differentiation behaviour that can be passed on with fidelity through many stem cell divisions. We have also identified a developmental “switch” that alters stem cell proliferation and self-renewal control in the post-natal period. We are now trying to elucidate the molecular mechanisms underlying each of these causes of variable stem cell behaviour using defined culture systems, gene transfer strategies, and genome-wide gene expression analyses.
Another goal is to investigate the molecular basis of the altered behaviour of the leukemic stem cells in patients with chronic myeloid leukemia, to develop new models of this disease in mice reconstituted with genetically modified human and murine stem cells and to identify new agents for their selective kill.
A third initiative is focused on extending the above approaches to the study of human breast cancer. We have pioneered the development of quantitative assays for normal mouse and human breast epithelial stem cells and these are being used to identify their distinguishing features and growth regulation. Studies to adapt these methods for application to human breast cancer are underway. The objective is to provide a basis for analyzing molecular and genetic determinants of breast cancer at the level of the breast cancer stem cell and thereby develop more rational, patient-targeted therapies.
Professor, Medical Genetics, University of British Columbia
Professor, Medical Genetics, UBC
Associate Member, Medicine, UBC
Associate Member, Pathology & Laboratory Medicine, UBC