New Jackson Laboratory Researcher Investigates Brain Development and Cancer
JAX® NOTES Issue 507, Fall 2007
Associate Staff Scientist Kyuson Yun PhD is one of the newest members of our scientific staff. She and her laboratory are focusing on the biology of normal and cancer stem cells in the breast and brain. Their long-term goal is to provide the molecular and cellular tools necessary for diagnosing and treating human disorders, such as cancer and neurological diseases, by manipulating stem cells. Says Yun, "Understanding the biology of stem cells is likely to have a huge impact on developing new treatments for cancer and neurodevelopmental/neurodegenerative disorders. However, we need a much better understanding of the mechanisms that regulate the maintenance, proliferation, and differentiation of stem cells. In addition, deciphering the molecular differences between normal and cancer stem cells will be very important in developing strategies that specifically target cancer stem cells."
Targeting Brain Cancer Stem Cell
The recent discovery of cancer stem cells in human brain and other solid tumors is a paradigm-shifting observation that provides hope and opportunities to develop a new generation of therapeutics that target these special cells. Although they constitute only a very small percentage of the total tumor mass, cancer stem cells give rise to all other cell types in the tumor and are the only cells that can initiate a tumor when transplanted. Dr. Yun is testing her hypothesis that eliminating these cells is both necessary and sufficient to block tumor growth. She remarks, "The tumor stem cells are slow-dividing and express genes that allow them to evade radio- and chemo-therapies that target the quickly dividing cancer cells. Since a small number of these surviving cells can re-initiate tumors, their existence may explain the recurrence of cancer even when the tumor mass appears to have been eliminated by surgery and chemotherapy."
Dr. Yun and her team recently showed that mouse models accurately replicate the pathobiology of human brain cancer, in particular that mouse brain tumors also contain cancer stem cells. Using a transgenic mouse model of oligodendroglioma (Tg(S100b-v-erbB)4496Waw), they showed that 1) cultured mouse cancer stem cells have cardinal features of somatic stem cells (self-renewal and multipotentiality), 2) tumor-initiating capacity is limited to a small subpopulation of cells called side-population cells, and 3) when transplanted in immune deficient mice, as few as 50 purified cancer stem cells can initiate tumors.Dr. Yun's research is progressing well. She has identified a subpopulation of cancer cells that have tumor-initiating capacity, and, by comparing and contrasting the molecular signatures of cancer stem cells and normal stem cells, she has discovered a gene signature that distinguishes cancer stem cells from normal stem cells and non-stem cancer cells (Harris et al. submitted). She is also generating new transgenic mouse models that will allow her to selectively kill putative cancer stem cells that express a molecular marker that identifies cancer stem cells in human brain and colon cancers. And, she is using mouse models of breast cancer to test the hypotheses that not all cancers contain cancer stem cells and that successful metastatic cancer cells are cancer stem cells.
Regulation of Normal Neural Stem Cells
To understand the genetic pathways that regulate normal neural stem cells during brain development and in the adult brain, Dr. Yun is studying the role of a family of transcription factors called the Id genes. Id genes have been shown to perform essential functions in many tissues during mammalian development and cancer. Recently, Dr. Yun and her colleagues found that, depending on the cell type in which they are expressed, the Id2 and Id4 genes can either stimulate or inhibit proliferation of neural cells. Although Id4 was known to be required for cell cycle progression and expansion of the early telencephalic
neuroepithelium, Dr. Yun discovered that, in post mitotic neurons of the cortex, it is also required to block aberrant cell cycle re-entry (Yun et al. 2004). Additionally, although there are many reports indicating that Id2 promotes proliferation, Dr. Yun and her colleagues recently observed that overexpression of Id2 in the neuroepithelium has the surprising effect of reducing neuroepithelial expansion, resulting in a smaller brain. Consistently, neural stem cells derived from Id4-deficient or Id2-overexpressing mice do not self renew as robustly as those derived from littermate controls. Dr. Yun's observations also indicate that Id genes regulate the maintenance of adult neural stem cells. She and her team are currently examining the molecular mechanisms underlying the apparently oppposing effects of Id gene mis-expression on the survival, proliferation, and differentiation of neural stem cells. Her team has also made the observation that ectopic expression of a ligand-independent, activated form of Notch1 results in increased apopotosis and defective self-renewal of neural stem cells. They are pursuing these observations to determine the genetic network that regulates neural stem cells in the developing brain.
Cell-based Therapies for Neurodevelopmental Disorders
Dr. Yun is also exploring a new area of research, identifying and manipulating alternative sources of stem cells for autologous transplantations. She is focusing on two rare neurodevelopmental disorders, Sly's disease and Krabbe's disease, using mouse models that recapitulate these human disorders. She and her team are isolating and manipulating cells from readily accessible tissue sources and culturing them into neural stem cell-like cells. Mutated or missing enzymes can be added to these manipulated cells before they are transplanted in host mice. Dr. Yun's team has identified a novel source of neural stem cells (from mouse and human tissues) and is testing them for cell-based therapy in these neurodevelepmental mouse models.
Dr. Yun received her BS in biology from Caltech in 1989 and her PhD in biology from Caltech in 1997. She then trained as a postdoctoral fellow at the University of California, San Francisco, and, most recently, as a Research Associate and then as an Instructor in the Department of Genetics at Dartmouth College, Hanover, N.H. Her work at The Jackson Laboratory will undoubtedly enrich our already diverse, energetic, and top-notch neuroscience and cancer research staff.
For more details and publications of Dr. Yun's work, please visit her Web site.
References
(Authors in bold are Jackson Laboratory scientists.)
Yun K, Mantani A, Garel S, Rubenstein J, Israel M. 2004. Id4 regulates neural progenitor proliferation and differentiation in vivo. Development 131:5441-8.
Harris MA, Yang H, Low BH, Shultz LD, Israel MA, Yun K. Identifying the brain cancer stem cell gene signature, submitted for publication.
