Ependymoma is the third most common pediatric brain tumor (supratentorial (ST) and posterior fossa (PF)) and the most common adult spinal tumor (SP). Surgery and irradiation are the predominant treatments since chemotherapy is ineffective in most patients; consequently, ependymoma is incurable in up to 40% of cases. Ependymomas from different regions of the CNS display disparate prognoses, transcriptional profiles and genetic alterations, suggesting they represent distinct molecular disease subgroups. This heterogeneity confounds efforts to study, model and treat these tumors. My previous project described a novel interspecies genomic approach that meticulously matched subgroup specific driver mutations, Ephb2 overexpression, with the appropriate cell of origin, embryonic neural stem cells (NSC), to model human ependymoma subgroups (Nature. 2010 Jul 29;466(7306):632-6). Building upon these studies, my laboratory is elucidating the mechanism by which Ephb2 transforms cerebral NSCs. Using a combination of stem cell culture assays and a mouse intracranial implantation model system we are dissecting the molecular pathways involved in disease development. This is a critical next step in understanding the biology and treatment of ependymoma. Consequently, we are undertaking a series of studies that will test the central hypothesis: ‘key components of the Ephb2 signaling system play a critical role in the transformation of cerebral NSCs into ependymoma’. We are testing this hypothesis by addressing two key questions:1. Which Ephb2 domains are required for transformation?2. What is the role of forward and reverse signaling in transformation?In order to answer these questions we are taking advantage of established Ephb2 point mutations as well as domain deletion constructs and evaluating their effects on NSC transformation using our stem cell culture and intracranial implant systems.