Chin Chiang, M.D.
Second-year funding 2010-2011
Medulloblastoma, the most common pediatric solid tumor, is characterized by its rapid progression and tendency to spread along the entire brain-spinal axis with poor clinical outcome. We have generated a novel mouse model of medulloblastoma by constitutively activating Shh signaling in the Gdf7-lineage. Previous studies have shown that Gdf7-expressing roof plate cells contribute to the hindbrain choroid plexus epithelium. Therefore, it is surprising that Shh pathway activation in Gdf7-lineage cells causes medulloblastoma. The objective of the proposal is to further characterize this mouse model with respect to cellular origin and function. We have made significant progress toward our goals. Through the analysis of our mouse model, we have published two method-based articles describing how to isolate medulloblastoma tumor stem cells and how to generate secondary tumors from them. We have also discovered that the apparently unipotent Gdf7-expressing roof plate cells in the hindbrain region, as previously reported, are in fact multipotent, contributing to many types of mature GABAergic and glutamatergic neuronal cells as well as glial cells. Our study, therefore, indicates that a roof plate cell lineage is susceptible to oncogenic transformation despite its relatively small contribution to the cerebellar cytoarchitecture. In this context, the CGNP features of Gdf7Cre/+; SmoM2 medulloblastomas indicate that within the spectrum of Gdf7 cell potency, acquisition of CGNP identity is obligatory during Hedgehog pathway mediated tumorigenesis. This work is currently submitted as a manuscript for review.
Publications
Huang, X., Ketova, T., Litingtung, Y. and Chiang, C. 2010. Isolation, Enrichment and Maintenance of Medulloblastoma Stem Cells. J. Vis. Exp., 2010 Sep 1;(43)
Huang, X., Sarangi, A., Ketova, T., Cooper, M. K., Litingtung, Y. and Chiang, C. 2010. Intracranial Orthotopic Allografting of Medulloblastoma. J. Vis. Exp., In press.
Huang, X., Cheng, Y.F., Sarangi, A., Ketova, T., Cooper, M.K., Litingtung, Y. and Chiang, C. 2010. Hindbrain roof plate cells are multipotent and susceptible to oncogenic transformation by deregulated Shh signaling. Submitted
Published in Isolation, Enrichment and Maintenance of Medulloblastoma Stem Cells. J. Vis. Exp., 2010 Sep 1;(43).