Power, Alexander Luc;
(2024)
Injury microenvironment signals regulate NF1-associated neurofibroma formation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Neurofibromas are benign peripheral nerve tumours that frequently arise in the context of the common tumour predisposition syndrome Neurofibromatosis Type 1 (NF1). The growth of these Schwann cell (SC)-derived tumours is driven by hyperactivation of Ras/MAPK signalling, a consequence of loss of function mutations to the NF1 tumour suppressor which encodes the key Ras negative regulator neurofibromin. However, although mutation to NF1 is the only genetic lesion needed for neurofibroma formation, multiple mouse models have demonstrated that additional input from the microenvironment is required for tumourigenesis. We have previously shown that Nf1 loss alone in murine adult SCs is insufficient for tumourigenesis, but that SC-specific Nf1 ablation (Nf1-/- SCs) combined with nerve injury consistently leads to tumour formation at the site of injury. This implied that tumour-promoting signals within the microenvironment of a damaged nerve are essential for tumourigenesis, among which transforming growth factor beta (TGF-β) was identified as a prime candidate. We therefore aimed to investigate the role of TGF-β in neurofibroma formation. In this thesis, we have demonstrated that TGF-β is the injury microenvironment factor required for neurofibroma formation, with ablation of the TGF-β receptor from Nf1-/- SCs resulting in failure to form tumours. Using our injury model to analyse the earliest stages of neurofibroma formation, we identified that, after injury, while WT SCs participate in nerve regeneration, many Nf1-/- SCs instead ‘escape’ the regenerating nerve, forming a tumour-initiating population in a TGF-β-rich environment. Mechanistically, we showed that TGF-β disrupts SC/axonal interactions and SC differentiation, allowing Nf1-/- SCs to remain in a tumour-like ‘repair’ state after injury, culminating in tumourigenesis. Targeting of TGF-β signalling using pharmacological inhibitors led to significantly reduced tumour formation, potentially identifying a promising novel therapeutic target in the treatment of NF1 and neurofibromas.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Injury microenvironment signals regulate NF1-associated neurofibroma formation |
| Language: | English |
| Additional information: | Copyright © The Author 2024. 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 > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10198804 |
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