Developmental signaling pathways are known to play important roles in normal neural stem cell (NSC) dynamics and can significantly alter the development of gliomas, highly aggressive brain tumours that arise from NSC-like tumour-initiating cells (TIC). Among these pathways, Hippo and Wnt signal transduction are implicated in the growth of glioma and undergo coordinated signaling in many pathological contexts, including colorectal cancer1. YAP is a transcriptional co-activator in the Hippo pathway that binds to b-catenin and regulates Dishevelled to inihibit Wnt/b-catenin signaling. Additionally, several components of the Wnt pathway are overexpressed in human gliomas, including Dishevelled2 and b-catenin2-3. Yet the mechanisms of YAP/Hippo signaling in Wnt pathway-mediated inhibition of gliomagenesis remain unexplored. Therefore, the impetus of this proposal is to reveal novel arenas of Hippo and Wnt interactions in glioma TICs. The overall hypothesis is that TICs, which drive growth of human glioma, retain responsiveness to Wnt signaling by altering cell fate decisions and that YAP/Hippo signaling plays a vital role in Wnt-dependent gliomagenesis. The current proposal comprises of two aims that address aspects of Hippo and Wn signaling in glioma TICs.
