The molecular role of non-canonical Notch signaling via Deltex-1 in high grade glioma

Abstract

Glioblastoma Multiforme is a WHO grade IV brain tumor with glial characteristics leading to more years of life lost than any other cancer. A better understanding of GBM biology and valid animal models are the two key elements to improved therapeutic results. We found Deltex1, which is part of an alternative Notch pathway, to activate both the PI3K/PKB and the MAPK/ERK pathway and to induce anti-apoptotic Mcl-1. DTX1 over-expression resulted in increased clonogenic and growth potential and also induced cell migration and invasion. Microarray gene expression analysis identified a DTX1-specific transcriptional program related to the changes in phenotype observed. Patients with low DTX1 levels have a favorable prognosis. Therefore, we propose the alternative Notch pathway via DTX1 as an oncogenic factor in glioblastoma. This could partially explain previous findings linking Notch status to prognosis wherein high Notch2 levels correlated with reduced patient survival. We found activated Notch2 in neural stem cells to induce glioma-inducing-cell features including increased proliferation, reduced apoptosis and astrocytic lineage commitment. These observations were found both in vitro and in vivo using a conditional mouse model. Together, these findings indicate an important role for Notch signaling (both canonical and non-canocical) in high grade glioma, offering a potential treatment target. We have also established an in vivo model of GBM which allowed us to analyze the efficacy of novel treatment regimens. Short term treatment of orthotopic xenograft gliomas in nude mice with histone deacetylase inhibitors and 2-deoxy-D-glucose resulted in prolonged survival, reduced tumor growth and induction of cancer cell apoptosis. Therefore, epigenetic reprogramming in combination with energy deprivation was found to have anti-tumor activity in vivo. In an independent project we identified GSK3β as a downstream target of Bmi1. GSK3β maintains a more stem cell like characteristic in GBM cells, potentially also in the glioma inducing cells. Several inhibitors to GSK3β exist and LiCl, which is often used in the clinic, correlates with reduced glioma incidence. Altogether, we believe we have added considerable knowledge on the biology of gliomas thereby helping to characterize the underlying events of gliomagenesis. Furthermore, we have established proof of principle for a novel treatment strategy in vivo.