Welcome to the home page of the Paddison Laboratory.
|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.
If you are interested in joining the Paddison Lab as an undergraduate, graduate student, postdoctoral fellow, or visiting scientist, please contact Patrick Paddison with a statement of your research interests and CV. We welcome applications from motivated individuals with an interest in bringing creative and interdisciplinary approaches to the study of stem cell and cancer biology.
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.
Hubert CG, Bradley RK, Ding Y, Toledo CM, Herman J, Skutt-Kakaria K, Girard EJ, Davison J, Berndt J, Corrin P, Hardcastle J, Basom R, Delrow JJ, Webb T, Pollard SM, Lee J, Olson JM, and Paddison PJ. Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. . Genes Dev. 27:1032-45, 2013.
Betschinger J, Nichols J, Dietmann S, Corrin P, Paddison PJ, Smith A. Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell 153: 335-47, 2013.
Ding Y, Hubert CG, Herman J, Corrin P, Toledo CM, Skutt-Kakaria K, Vazquez J, Basom R, Zhang B, Risler JK, Pollard SM, Nam DH, Delrow JJ, Zhu J, Lee J, DeLuca J, Olson JM, Paddison PJ. Cancer-Specific requirement for BUB1B/BUBR1 in human brain tumor isolates and genetically transformed cells. Cancer Discov. 3:198-211, 2013.
Chen X, Skutt-Kakaria K, Davison J, Ou YL, Choi E, Malik P, Loeb K, Wood B, Georges G, Torok-Storb B, Paddison PJ. G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. Genes Dev. 26:2499-511, 2012.
Paddison PJ. RNA interference in mammalian cell systems. In: RNA interference. Current Topics in Microbiology and Immunology. Paddison PJ, Vogt PK (eds.). Springer Press, 2008.
Paddison PJ, Silva JM, Conklin DS, Schlabach M, Li M, Gnoj L, Balija V, O’Shaughnessy A, Scobie K, Aruleba S, Chang K, Westbrook T, Sachidanandam R, McCombie WR, Elledge SJ, Hannon GJ. A resource for large-scale RNAi based screens in mammals. Nature 428: 427-431, 2004.Paddison PJ, Hannon GJ. RNA interference: The New Somatic Cell Genetics? Cancer Cell 2:17-23, 2002.
Site Last Updated: 28 August 2013