Pollard, Steven

Carragher, Neil

Robertson, Faye Louise

Cancer Research UK

2021-10-18T12:03:29Z

2021-10-18T12:03:29Z

2021-07-31

The balance of stem cell quiescence versus proliferation must be tightly regulated under normal homeostasis and becomes disrupted in cancers. The brain cancer glioblastoma is driven by cells with neural stem cell characteristics. These glioblastoma stem cells (GSCs) can reside in dormant, quiescent and proliferative states, yet the molecular transitions between these remain poorly understood. Quiescent GSCs are refractory to anti-mitotic cytotoxic therapies, and contribute to regrowth of the tumour; therefore elucidating molecular pathways that control GSC exit from quiescence may uncover new therapeutic strategies. The role of Wnt signaling in GBM has remained enigmatic. Here I show that the transcription factor FOXG1, which is frequently overexpressed in GSCs, cooperates with Wnt signaling to drive efficient exit from quiescence. However, Wnt signaling is dispensable once GSCs are fully proliferative. Using a phenotypic chemical screen (303 small molecule regulators of stem cell related pathways) I identified a potent synergy between glycogen synthase kinase 3 (GSK3) inhibitors and FOXG1 in driving exit from NSC quiescence. Pharmacological and genetic perturbations confirmed that this was due to activation of the Wnt/beta catenin pathway. The FOXG1/Wnt synergy is also relevant in vivo, and in human glioblastoma cell models. Mechanistically, these data suggest that the excessive FOXG1 both leads to an accumulation of beta-catenin and sequesters the Wnt/TCF co-repressor Groucho/TLE, thereby derepressing Wnt/beta catenin target genes and enabling their maximal activation. I conclude that FOXG1 and Wnt cooperate in the critical process of exiting the quiescent state. These findings suggest inhibition of Wnt signaling will have limited impact on the proliferative GSC compartment, but may be critical in preventing reactivation of the quiescent cells that drive regrowth of the tumour after chemo- and radiotherapy.

https://hdl.handle.net/1842/38178

http://dx.doi.org/10.7488/era/1445

en

The University of Edinburgh

Robertson, F.L., Marqués-Torrejón, M.-A., Morrison, G.M., and Pollard, S.M. (2019). Experimental models and tools to tackle glioblastoma. Dis. Model. Mech. 12.

glioblastoma

FOXG1

Wnt signalling pathway

glioblastoma stem cells

GSK3 inhibitors

Regulation of neural stem cell and glioblastoma stem cell quiescence by FOXG1 and Wnt/beta-catenin

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy