Transcriptional Differences between Normal and Glioma-Derived Glial Progenitor Cells Identify a Core Set of Dysregulated Genes

Abstract

SUMMARY Glial progenitor cells (GPCs) are a potential source of malignant gliomas. We used A2B5-based sorting to extract tumorigenic GPCs from human gliomas spanning WHO grades II-IV. mRNA profiling identified a cohort of genes that distinguished tumor-initiating progenitor cells (TPCs) from A2B5+ GPCs isolated from normal white matter. A core set of genes and pathways was substantially dysregulated in A2B5+ TPCs, that included the transcription factor SIX1, and its principal co-factors, EYA1 and DACH2. shRNAi silencing of SIX1 inhibited the expansion of glioma TPCs in vitro and in vivo, suggesting a critical and unrecognized role of the SIX1-EYA1-DACH2 system in glioma genesis or progression. By comparing the expression patterns of glioma TPCs to normal GPCs, we have identified a discrete set of pathways by which glial tumorigenesis may be better understood, and more specifically targeted.

Lineage, fate, and fate potential of NG2-glia

“…Recent transcriptomic profiling studies have revealed that NG2 cells express a number of genes previously considered as neuron-specific genes (Table 1). Notably, Calretinin (Calb2) and Doublecortin (Dcx) used in previous NG2 cell fate and lineage analyses (He et al, 2001; Clarke et al, 2012; Tsoa et al, 2014; Jablonska et al; 2010 Dayer et al, 2005) as well as a number of genes encoding presynaptic terminal proteins are detected at significant levels in NG2 cells in five microarray and one RNA-sequence databases (Nielsen et al, 2006; Cahoy et al, 2008; Lau et al, 2008; Wang et al, 2013; Auvergne et al, 2013; Zhang et al, 2014; Moyon et al, 2015). Other genes that are actively transcribed in telencephalic NG2 cells include the interneuron proteins Gephyrin and Gad1, which may reflect their developmental history.…”

The SIX1-EYA transcriptional complex as a therapeutic target in cancer

“…Both SIX1 and EYA are overexpressed in multiple cancer types including ovarian 53, 75 , breast 77 , glioblastomas 86 , leukemia 81 , and Wilms’ tumor 72 . Moreover, we found that overexpression of either SIX1 or EYA commonly correlated with recurrence, metastasis, and a decreased overall survival in a variety of tumor types, using the Oncomine cancer microarray database 19 .…”

Glial Progenitors as Targets for Transformation in Glioma

“…Liu et al, 2011). As A2B5-expressing GSCs become more mesenchymal with grade (Auvergne et al, 2013), it is possible that cell-surface proteins on GSCs change during the disease progression or following therapy (Bhat et al, 2011, 2013; K. V Lu et al, 2012; Mao et al, 2013).…”

“…The authors show that the WNT inhibitor secreted frizzled-related protein 1 (SFRP1) effectively reduced proliferation and self-renewal of GSCs (Sandberg et al, 2013). Furthermore, WNT components are more prominently expressed in A2B5+ cells isolated from GBM versus lower-grade gliomas (Auvergne et al, 2013). During normal development, WNT influence the timing and efficacy of OPC generation in the telencephalon (Langseth et al, 2010).…”

“…ErbB3 is highly expressed on both human OPCs and proneural glioma cells expressing A2B5 (Auvergne et al, 2013; Sim et al, 2011; Verhaak et al, 2010). ErbB3 and EGFR regulate survival in OPCs (Flores et al, 2000; Ivkovic, Canoll, & Goldman, 2008) (Figure 2).…”