MYCN is a transcription factor and a potent mitogen with essential roles in normal development. Mis-expression of MYCN occurs commonly in childhood brain tumors of the cerebellum, medulloblastoma but also in adult brain tumors of the forebrain, glioma. My group is exploring the role for MYCN in these malignant tumors with focus on identifying cells of brain tumor origin as well as understanding critical signaling pathways involved in tumor initiation and tumor progression.
Our present research involves studying MYCN and its role in primary neural stem cells (NSCs) that we can culture from different brain regions. We recently found that stabilization of MYCN is important for brain tumor initiation and now investigate how MYCN controls other proteins in NSCs. In particular we are studying if MYCN regulates the transcription factor SOX9 that is involved in glial fate determination in the brain.
We and others have recently found that the transcription factor SOX9 could mark a dependence on the protein Sonic Hedgehog (SHH) in human medulloblastoma cells. SHH controls a developmental pathway that can be targeted by various promising cancer drugs and it has previously been shown that SHH can control MYCN levels in cells of the cerebellum.
We are now using ChIP sequencing to further identify targets of SOX9 in NSCs and in our MYCN-driven tumor models (Swartling et al. Genes & Dev., 2010; Swartling et al. Cancer Cell, 2012). These brain tumor models (Figure 1) represent new interesting tools that can be used to study treatment strategies for targeting MYCN that can give further clues on how to treat this disease. In particular we are studying new therapies that targets MYCN protein stabilization that we think could be new promising treatments for these brain tumors.
Another project involves studying primary cilia loss during brain tumor formation. Primary cilia are tiny microtubule-based organelles. Every normal stem cell in the brain has a primary cilium at its surface (Figure 2A). There is a strong correlation with lack of cilia and the most aggressive types of brain tumors (Figure 2B). We are now studying how oncogenes downregulate cilia from the surfaces of cultured neural stem cells and if this also occurs in tumors carrying other oncogenes.