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Title: Wnt signalling in the Ewing's sarcoma family of tumours
Author: Shaw, Lucy Abigail
ISNI:       0000 0004 5349 9108
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2014
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Ewing’s sarcoma family of tumours (ESFT) are aggressive tumours with a tendency to metastasise, which is associated with poor outcome. ESFT are characterised by an EWS-ETS gene rearrangement, most commonly EWS-FLI1. However, the mechanism of tumour formation is poorly understood and the cell of origin unclear. Since Wnt signalling is frequently deregulated in pathological conditions including cancer I have examined the potential role of Wnt signalling in ESFT cell lines and two novel in vitro models of ESFT development. Components of the Wnt signalling pathway were expressed in all 6 ESFT cell lines studied. A lentiviral-based luciferase assay measuring TCF/LEF mediated signalling was successfully developed and demonstrated that the canonical Wnt signalling pathway is active in ESFT cell lines. Assays developed to investigate the activity of the noncanonical Wnt signalling pathway indicated that active Rac1 is expressed in some ESFT cell lines, and that ESFT cell lines are highly migratory. Two complementary model systems were utilised to investigate Wnt signalling in the initiation of ESFT. Firstly, analysis of reprogrammed ESFT cells showed an increase in response of the canonical Wnt signalling pathway to Wnt3A, and an increase in active Rac1 expression. Furthermore Wnt signalling components were differentially expressed in reprogrammed cells. The induction of EWS-FLI1 expression in human embryonic stem (hES) cells increased canonical Wnt signalling and expression of active Cdc42. These cells had an altered phenotype and were more migratory. EWS-FLI1 expression also resulted in differential expression of Wnt signalling components including DKK2, DKK4, FZD8, Wnt4 and Wnt5A. These data demonstrate that both the canonical and noncanonical Wnt signalling pathways may be important in the initiation of ESFT. Further elucidation of the role of these pathways and the individual components in tumour development could inform the development of novel therapeutics that could prevent tumour metastasis and relapse.
Supervisor: Burchill, Susan ; Payne, Helen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available