Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

SIMPLE SUMMARY: Glioblastoma stem cells are a unique population of tumor cells that contribute to tumor growth, invasion, and resistance to chemotherapy and radiation therapy. These stem cells are capable of self-renewal and proliferation. Traditional treatment strategies that target glioblastoma often fail to eradicate these stem cells, contributing to tumor recurrence. Dysregulation of several critical signaling pathways drive the oncogenic nature of glioblastoma stem cells and represent attractive therapeutic targets. Additionally, these stem cells possess a high mutation rate and feature epigenomic changes that alter the landscape of their genomic expression. Here, we review the phenotypic characteristics of glioblastoma stem cells, their interactions with the tumor microenvironment, critical signaling pathways, and epigenomic landscape of glioblastoma stem cells. Therapeutic targets are discussed in the context of these pathways and mutations. A multi-pronged therapeutic approach will likely be needed to simultaneously target multiple pathways and molecules to overcome tumor resistance mechanisms. ABSTRACT: Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.