HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment

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

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

Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma

Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/ RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention