Tag: Hui Zong

Presenter: Kelsey Wahl

Medulloblastoma is the most common type of malignant brain tumor in children. During cerebellar development, granule neuron precursor cells (GNPs) proliferate along the external germinal layer in response to the sonic hedgehog signaling pathway. Mutations in the sonic hedgehog signaling receptor patched (Ptc) lead to tumors in the cerebellum through over-proliferation of GNPs. Over 50% of mice with the mutation develop foci of ectopic cells on the surface of the cerebellum between 3-6 weeks. Observations suggest that the ectopic cells may represent a pre-neoplastic stage of medulloblastoma. Although GNPs are unipotent progenitors that only give rise to granule neurons, lineage tracing studies in our lab have indicated that tumorigenic GNPs can also differentiate into glial cells. To further understand this fate switch and determine if it occurs prior to tumor formation, we looked for glia presence in Ptc pre-neoplastic lesions (PNLs). The appearance of glia cells in the earliest stages of tumor formation could provide insight into their potential supporting role in the tumor and in tumor cell transformation.

Glioblastoma is the most common and aggressive type of malignant brain tumor. Due to the tumor cell’s ability to disperse through- out the brain, their resistance to traditional chemotherapy and high rate of tumor relapse, current research is focusing on determining and designing therapies against the tumor cell-of-origin. In order to determine the cell of origin in these tumors, labeled mutant cells were generated through the use of mosaic analysis with double markers (MADM) allowing our lab to track the entire tumorigenic process in vivo and determine which cell types were giving rise to tumors. It was found that oligodendrocyte precursor cells (OPCs) were the primary cell type to show overexpansion and eventually give rise to a malignant tumor. It was hypothesized that by ablating the OPC cell population, using a genetic tool, one could prevent tumor formation or slow tumor growth. OPC specific thymidine kinase (TK) in conjunction with the drug Ganciclovir (GCV) was used in the hopes of causing OPC death. However, when end stage tumors were analyzed it was found that TK expression had been lost within the tumor cells, but not mutant OPCs outside of the tumor region. DNA analysis showed that the loss of the TK transgene had occurred on a genomic level, suggesting that a region of genomic DNA had been lost. The goal of this study is to characterize when the loss of TK occurs. Analysis of small tumors will reveal if TK loss is necessary for tumor growth or if it is lost as a function of tumor growth.