Patrick J. Paddison
Appointments and Affiliations
FUNCTIONAL GENOMICS OF STEM CELL AND CANCER CELL BIOLOGY
The Paddison Lab uses functional genomics to probe the underlying biology of mammalian stem and progenitor cells. Our primary goal is to define the biological units of self-renewal, expansion, and lineage commitment in model stem cell systems, including: embryonic stem cells, hematopoietic stem cells, neural progenitor cells, and brain tumor initiating cells (i.e., brain tumor stem cells). We are particularly interested in the understanding the molecular mechanisms that allow stem cells to maintain their unique identity and developmental potential.
- Glioblastoma multiforme (GBM) as a model cancer system. For most of our cancer work we experiment with cells from patients with Glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We routinely isolate and culture tumor-initiating GBM stem cells (GSCs) from brain tumor samples, which retain the development potential and specific genetic alterations found in the patient’s tumor. These cells allow direct experimental access to the patient's tumor and allow us to address biological and clinically-oriented questions regarding tumor initiation and maintenance. For example, we have begun to catalog cancer-specific molecular vulnerabilities in GSC in "compare and contrast" studies with non-transformed neural stem cells (NSCs), which are candidate cells-of-origin for GBM. These studies have led to the identification of novel therapeutic strategies for GBM, which are being pursued in collaboration with Dr. Jim Olson (Clinical Research Division, FHCRC).
- Human hematopoietic stem cell expansion and differentiation. Another stem cell system we work with is human hematopoietic stem and progenitor cells (HSPCs). These cells can be routinely isolated as mixed CD34+ progenitor pools from peripheral human blood or bone marrow in sufficient quantities for ex vivo lineage studies and experimentation. We are currently focused on understanding stem cell commitment to erythroid and megakaryotic lineages, which give rise to red blood cells and platelets. We are examining roles for particular epigenetic marks (e.g., H3K9me2) and also epigenetic regulators (e.g., histone demethylases) during specification of these lineages. One clinical goal is to direct lineage choice to help treat post-HSC transplantation cytopenias, a goal we pursue in collaboration with Dr. Beverly Torok-Storb (Clinical Research Division, FHCRC).
- Embryonic stem cell expansion and differentiation. Embryonic stem cells (ESCs) are cell lines derived from the inner cell mass (ICM) of blastocyst stage mammalian embryos. They can grow indefinitely in culture and give rise to cells of all three embryonic germ layers as well as germ cells. For these reasons ES cells hold great promise for regenerative medicine. While some molecular details of the ESC self-renewal network have emerged, more in depth knowledge will be required to facilitate future ESC-based clinical applications. We have now identified several novel activators and repressors of ESC self-renewal gene expression through performing multiple RNAi screens. We are now characterizing several genes with roles in facilitating ESC fate and integrating distinct modes of epigenetic regulation.
Honors and Awards
- Department of Defense
- National Cancer Institute
- The National Institute of Diabetes and Digestive and Kidney Diseases
- Pew Scholars in the Biomedical Sciences
- Phi Beta Psi Sorority