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dc.contributor.advisorPollard, Steven
dc.contributor.advisorCarragher, Neil
dc.contributor.authorRobertson, Faye Louise
dc.date.accessioned2021-10-18T12:03:29Z
dc.date.available2021-10-18T12:03:29Z
dc.date.issued2021-07-31
dc.identifier.urihttps://hdl.handle.net/1842/38178
dc.identifier.urihttp://dx.doi.org/10.7488/era/1445
dc.description.abstractThe 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.en
dc.contributor.sponsorotheren
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionRobertson, 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.en
dc.subjectglioblastomaen
dc.subjectFOXG1en
dc.subjectWnt signalling pathwayen
dc.subjectglioblastoma stem cellsen
dc.subjectGSK3 inhibitorsen
dc.titleRegulation of neural stem cell and glioblastoma stem cell quiescence by FOXG1 and Wnt/beta-cateninen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2022-07-31en
dcterms.accessRightsRestricted Accessen


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