Elevated FOXG1 in glioblastoma stem cells cooperates with Wnt/β-catenin to induce exit from quiescence.

Glioblastoma (GBM) stem cells (GSCs) display phenotypic and molecular features reminiscent of normal neural stem cells and exhibit a spectrum of cell cycle states (dormant, quiescent, proliferative). However, mechanisms controlling the transition from quiescence to proliferation in both neural stem cells (NSCs) and GSCs are poorly understood. Elevated expression of the forebrain transcription factor FOXG1 is often observed in GBMs. Here, using small-molecule modulators and genetic perturbations, we identify a synergistic interaction between FOXG1 and Wnt/β-catenin signaling. Increased FOXG1 enhances Wnt-driven transcriptional targets, enabling highly efficient cell cycle re-entry from quiescence; however, neither FOXG1 nor Wnt is essential in rapidly proliferating cells. We demonstrate that FOXG1 overexpression supports gliomagenesis in vivo and that additional β-catenin induction drives accelerated tumor growth. These data indicate that elevated FOXG1 cooperates with Wnt signaling to support the transition from quiescence to proliferation in GSCs. [Display omitted] • A small-molecule screen reveals synergy between FOXG1 and GSK3 inhibition on quiescence exit • Genetic and pharmacological approaches confirm the role of Wnt in the synergy • FOXG1 enhances Wnt-driven transcriptional targets and represses WIF1 • Elevated FOXG1 and β-catenin in a GBM model drive accelerated growth and reduced survival Glioblastomas contain quiescent stem cells expressing high levels of FOXG1. Robertson et al. identify a synergistic interaction between FOXG1 and Wnt/β-catenin signaling that drives exit from quiescence in vitro and accelerated tumor growth in vivo. They show that FOXG1 enhances Wnt transcriptional targets and represses the Wnt inhibitor WIF1. [ABSTRACT FROM AUTHOR]