Gliomas are highly heterogeneous, incurable adult brain tumors. They are classified in various grades depending on their aggressiveness, with glioblastoma (GBM) being extremely invasive with an average patient life span of about one year after detection. GBMs can either arise de novo (primary GBM) or derive from low-grade glioma progression (secondary GBM). The mechanisms leading to progression of low-grade gliomas to GBM are still poorly understood. In addition, the failure of existing therapies may be due to the existence of glioma stem cells (GSCs) that are tumorigenic, radio- and chemo-resistant and capable of inducing recurrence. Our major goal is to elucidate the mechanisms that regulate glioma progression, especially those pathways required for cell self-renewal and invasion. Gene transcriptional profiling of high-grade gliomas has identified distinct molecular subtypes, including a mesenchymal subtype that consists of invasive tumors with a poor prognosis. We have shown that RP58 (ZNF238, ZFP238) acts as a tumor growth inhibitor in glioma cell lines. RP58 is a transcription factor required for brain development and neuronal differentiation. In addition, our preliminary data indicate that the reduction of RP58 expression correlates with increased glioma aggressiveness, including acquisition of a mesenchymal phenotype. Our overall hypothesis is that RP58 acts to inhibit glioma growth, stemness and invasion in part by repressing a mesenchymal gene signature, and that loss of RP58 is a critical event in glioma formation and/or progression and will be addressed with the following aims:
Aim1 : Determine the function of RP58 in glioma stem cells.
This aim will test the role of RP58 in glioma growth and invasion in vitro using primary glioma stem cell cultures and in vivo using orthotopic xenografts of glioma stem cells in mice.
Aim2 : Determine whether loss or reduced RP58 expression in mice contributes to brain tumor formation and/or invasion. Using genetic mouse models, we will test the hypothesis that reduction or deletion of Rp58 is sufficient for glioma formation and/or invasion in mice.
Aim 3. Determine the mechanisms involved in RP58 function to antagonize GSC self-renewal and/or glioma invasiveness? In this aim we will decipher the molecular mechanisms required for RP58 to regulate the self-renewal capacity of normal and cancer progenitors, its function in regulating mesenchymal properties in brain cells, and how these two processes are linked in gliomas. This project will address key aspects of glioma stemness, and aggressiveness, with a focus on a novel regulator of glioma progression. Completion of this project will identify novel mechanisms underlying glioma development and identify alternative targets for therapeutic intervention.
Our overarching goals are to develop the best innovative and safe therapies for brain tumors. Glioma, the most malignant and invasive adult brain tumor, has no optimal therapy. New molecular targets and approaches for clinical intervention are thus critically needed to increase the survival rate and reduce side effects. The completion of our project will greatly contribute to decipher how brain tumors become more aggressive. They will lead to an extensive understanding of the molecular and cellular nature of glioma and help us design better and safer therapies.
