- Normal Hematopoietic and Leukemic Stem Cells – Generation, Isolation, Functional and Molecular Characterization, Expansion and Regulation
- Normal and Malignant Human Breast Stem Cells – Generation, Isolation, Functional and Molecular Characterization, Expansion and Regulation
A major part of our work is currently focused on investigating the molecular mechanisms that intrinsically determine and extrinsically regulate the properties of quiescence, viability, self-renewal and lineage restriction of primitive human hematopoietic cells and how these may be altered in cells that produce lethal leukemic populations in immunodeficient mice. We have developed and deploy a variety of single cell division and clonal tracking methods that allow biological readouts to be coupled to directly measured molecular (epigenetic, transcriptional and protein/signaling) features of individually assessed starting cells by integrating shared surface phenotype data. We are now using these combined approaches to examine the effects of developmental and aging associated changes on the biological properties of primitive human hematopoietic cells, how these are regulated by different culture and xenotransplant conditions, how these may be perturbed by defined oncogenic manipulations and how these may be specifically targeted
A similar and parallel initiative is focused on extending the above approaches to an analysis of the cells that comprise the normal adult human mammary gland and the mechanisms that cause them to become transformed to create breast cancer. We have pioneered the development of methods to isolate and quantitatively assay the functional growth and differentiation properties in vitro and in xenografted mice of multiple normal human mammary cell types as well as several protocols for their rapid transformation by lentiviral transduction of defined oncogenic cDNAs. We are now using a similar panoply of combined molecular and biological measurements of the starting cells and their progeny to discover critical vulnerabilities of cells acquiring different degrees of aggressive malignant behaviour.