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Investigating the role of dual specificity phosphatases in neuroblastoma

Thompson, Elliott; (2022) Investigating the role of dual specificity phosphatases in neuroblastoma. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Neuroblastoma (NB) is a cancer of the developing neural crest that accounts for 7-10% of paediatric malignancies worldwide. Phosphotyrosine signalling is an integral aspect to neural crest cell development and the progression of NB. Protein tyrosine phosphatases (PTPs) are important regulators of these pathways and therefore their dysregulation can perturb NB cell survival and neuronal differentiation. The dual specificity phosphatases (DUSPs) are a subgroup of PTPs increasingly linked to tumorigenesis. Hence, the aim of this project was to understand the molecular function of DUSPs in NB and whether they can promote NB cell growth. I hoped this would reveal phosphatase enzymes that could serve as novel molecular targets in NB. An initial loss-of-function siRNA screen was performed to identify growth-promoting DUSPs in NB cells. Various candidate DUSPs were investigated further using CRISPR/Cas9 technology. Although in many cases CRISPR/Cas9-mediated genetic depletion did not reproduce siRNA knockdown findings, loss of DUSP6 or DUSP3 did suppress NB cell growth. However, the molecular function of DUSPs in NB cells remained elusive as individually, they did not appear to affect the MAP kinase or AKT pathways. In parallel, the therapeutic potential of a dual DUSP1/6 inhibitor, BCI, was investigated in NB. As in other cancer models, BCI demonstrated potent cytotoxicity in multiple NB cell lines. However, depletion of DUSP1 and DUSP6 did not influence BCI cytotoxicity, therefore we concluded BCI was hampered by multiple off-target effects. Lastly, I investigated whether DUSPs are important to oncogenic ALK signalling in ALK-mutated NB cells. Promisingly, removal of DUSP6 sensitised NB cells to ALK inhibition, however this effect was not rescued by re-introduction of exogenous DUSP6. A phosphoproteomic screen demonstrated ALK-mutated NB cells may have a biochemical co-dependency on ALK and DUSP6. Elucidating the DUSP6/ALK relationship further could identify novel pathways that could be therapeutically targeted alongside ALK.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating the role of dual specificity phosphatases in neuroblastoma
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10148906
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