Mb-107rest Elevation Unrestrains SHH Signaling in Medulloblastoma

Abstract

Medulloblastoma (MB) is a malignant pediatric brain tumor characterized by poor neuronal differentiation. The RE1 Silencing Transcription Factor (REST), a repressor of neurogenesis, is overexpressed in human MBs. The elevated expression of REST in a subset of patients with desmoplastic MB is associated with poor prognosis. To understand the underlying mechanisms, we generated a novel knock-in mouse expressing human REST transgene in a conditional manner in granule cell progenitors (GCPs), the cells of origin of sonic hedgehog (Shh) driven MB. Mice with constitutive activation of sonic hedgehog signaling and REST elevation (REST KI /Ptc +/-) in their GCPs developed tumors with a significant decrease in latency and increase in penetrance. We observed that 100% of REST KI /Ptc +/-animals developed heterogeneously proliferative and undifferentiated tumors with a striking increase in neural stem cell marker expression compared to tumor-bearing Ptc +/-animals. Mechanistic studies revealed direct transcriptional repression of Ptc by REST, which caused a total loss of Ptc expression in Ptc haploinsufficient GCPs. REST elevation in Ptc +/-GCPs also promoted significant Gli-1 dependent upregulation of the brain specific isoforms of Akt, and activation of AKT signaling. Consistent with this, 100% of REST KI /Ptc +/-animals developed highly vascularized, infiltrative tumors with a propensity for leptomeningeal dissemination. Thus, our studies suggest that REST elevation and constitutive Shh activation cooperatively drive an aggressive disease course by deregulating proliferation and driving the expansion of a highly undifferentiated cell population, with potential to promote rapid tumor growth and tumor dissemination.