The Role of Hippo Signalling in Merlin Null Tumours of the Nervous System

Abstract

Meningiomas and schwannomas are mostly benign tumours of the nervous system that currently have no clinically approved treatments apart from surgical resection. The tumour suppressor Moesin-Ezrin-Radixin-Like Protein (Merlin) is deleted in 50-60% and 70% of meningiomas and schwannomas respectively. The Hippo pathway is an evolutionarily conserved pathway that has been shown to control tissue size by contactmediated growth inhibition. Previous studies have shown that there is aberrant nuclear activity of yes-associated protein (YAP) and transcriptional coactivator with PDZbinding motif (TAZ), the co-transcriptional activators of the Hippo pathway in Merlinnull meningioma and schwannoma. Nuclear YAP and TAZ activate transcription, primarily by binding to the TEAD family of transcription factors, which has been linked to multiple tumour phenotypes. Here we aim to show that aberrant Hippo pathway activity in Merlin null meningioma and schwannoma can be targeted either genetically or pharmacologically to reduce tumour proliferation. We used a combination of in vitro and in vivo approaches, including primary tumour cell culture and Merlin null mouse models, to establish the role of Hippo signalling in Merlin null meningioma and schwannoma and to identify therapeutic targets. We saw that there was increased nuclear localisation of YAP in primary meningioma cells, and that knockdown of YAP or TAZ reduces proliferation in both meningioma and schwannoma cells. We used novel inhibitors of TEAD palmitoylation which disrupted the interaction between TEAD proteins and YAP/TAZ, leading to reduction of proliferation in meningioma and schwannoma. Through an RNA sequencing screen, we identified that the cancer stem cell marker ALDH1A1 is strongly upregulated in multiple meningioma and schwannoma models; v inhibition of ALDH1A1 reduced proliferation in primary meningioma and schwannoma cells. YAP and TAZ both transcriptionally activate TEAD family members, leading to transcription of genes which drive tumour phenotypes. In summary, we have characterised aberrant Hippo pathway activity in Merlin null meningioma and schwannoma, exploring the mechanisms by which loss of Merlin drives tumour progression, and explored therapeutic options that target such pathways. This thesis has provided evidence that pharmacological disruption of TEAD transcription is an effective way of reducing proliferation in Merlin null schwannoma and meningioma, thus provides a foundation for further studies testing inhibitors of TEAD palmitoylation in a schwannoma and meningioma in vivo mouse models.