In addition to specifying normal brain development and maintenance, neural stem cells are also important for the genesis and continued growth of brain tumors. Using primary cell culture systems in vitro and novel genetically-engineered mice in vivo, we have identified two distinct populations of stem cells critical for low-grade brain tumors in children.
First, we have shown that pediatric brain tumors arise from neural stem cells in a brain region-specific manner, such that not all germinal zones contain the cells of origin for low-grade gliomas arising either in the context of NF1 (optic gliomas) or sporadically when caused by genomic rearrangements of the BRAF gene (cerebellar gliomas).
Second, we have leveraged novel genetically-engineered mice to identify glioma stem cells important for low-grade optic glioma maintenance. These glioma stem cells acquire new molecular and functional properties that not only reveal adaptive mechanisms underlying resistance to conventional and biologically-targeted therapies, but also newly expressed genes that allow these stem cells to survive in response to stress conditions existing in the tumor and in response to treatment.
Current projects in the Gutmann research laboratory are focused on defining the innate molecular and cellular properties that allow some, but not all, progenitor cells to serve as the cells of origin for brain cancer using both in vitro and in vivo approaches. In addition, we continue to leverage low-grade glioma stem cells as tractable model systems to understand the unique properties of these cancer-maintaining cells relevant to improved therapies for brain tumors.