Oncogenic activity of SOX1 in glioblastoma

Idoia Garcia,Larraitz Egaña,Steven Pollard,Leire Moreno-Cugnon,Estefania Carrasco-Garcia,Paula Aldaz,Sergio Torres-Bayona,Jelena Marjanovic Vicentic,Angel Rubio,Laura Garros-Regulez,Milena Stevanovic,Nicolas Sampron,Ander Matheu,Juncal Aldaregia

doi:10.1038/srep46575

Abstract

Glioblastoma remains the most common and deadliest type of brain tumor and contains a population of self-renewing, highly tumorigenic glioma stem cells (GSCs), which contributes to tumor initiation and treatment resistance. Developmental programs participating in tissue development and homeostasis re-emerge in GSCs, supporting the development and progression of glioblastoma. SOX1 plays an important role in neural development and neural progenitor pool maintenance. Its impact on glioblastoma remains largely unknown. In this study, we have found that high levels of SOX1 observed in a subset of patients correlate with lower overall survival. At the cellular level, SOX1 expression is elevated in patient-derived GSCs and it is also higher in oncosphere culture compared to differentiation conditions in conventional glioblastoma cell lines. Moreover, genetic inhibition of SOX1 in patient-derived GSCs and conventional cell lines decreases self-renewal and proliferative capacity in vitro and tumor initiation and growth in vivo. Contrarily, SOX1 over-expression moderately promotes self-renewal and proliferation in GSCs. These functions seem to be independent of its activity as Wnt/β-catenin signaling regulator. In summary, these results identify a functional role for SOX1 in regulating glioma cell heterogeneity and plasticity, and suggest SOX1 as a potential target in the GSC population in glioblastoma.

Highlights

Glioblastoma remains the most common and deadliest type of brain tumor and contains a population of self-renewing, highly tumorigenic glioma stem cells (GSCs), which contributes to tumor initiation and treatment resistance
Significant advances have been made in the identification of the molecular mechanisms underlying the pathobiology and intratumoral heterogeneity of glioblastoma[4,6], further elucidation of the developmental programs governing glioma stem cells (GSCs) and glioblastoma progression is required in order to accelerate the development of urgently needed novel therapeutic targets and treatments
We studied SOX1 expression in the GBM data from the The Cancer Genome Atlas (TCGA) and found that its levels were heterogeneous within the different samples (Fig. 1C)

Summary

Introduction

Glioblastoma remains the most common and deadliest type of brain tumor and contains a population of self-renewing, highly tumorigenic glioma stem cells (GSCs), which contributes to tumor initiation and treatment resistance. To directly explore the role of SOX1 in the activity of GSCs, we knocked-down SOX1 expression in a patient-derived cell line (GNS166) with two independent shRNAs. Effective inhibition of SOX1 was demonstrated with qRT-PCR when using both shSOX1 constructs (sh[1] and sh5) (Fig. 3A).

Results

Conclusion