Identification of biomarkers for development of NF1-associated malignant peripheral nerve sheath tumours

Rad, Ellie 2015. Identification of biomarkers for development of NF1-associated malignant peripheral nerve sheath tumours. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Therapeutic options are currently limited for Neurofibromatosis type 1 (NF1) associated-malignant peripheral nerve sheath tumours (MPNSTs). MPNSTs are characteristically aggressive and the major cause of death in NF1 patients. Clinical trials using single drug agents to treat MPNSTs have so far been unsuccessful, which could be attributed to high levels of intra-tumoural molecular heterogeneity. To explore common cellular migratory and invasive signalling properties within the heterogeneous NF1-MPNST population, we utilised four different MPNST-derived cell lines, ST8814, S462, S1844.1 and S1507.2. MET has previously been shown to be elevated in MPNST cells and is thought to promote their cellular migration and invasion. Interestingly, we report variation in MET gene expression and protein levels in a variety of MPNST derived cell lines. MET inhibitors were effective at suppressing the migration and invasion of cell lines with elevated MET protein levels but not those without. Importantly, targeted inhibition of STAT3 suppressed cell migration, invasion and tumour formation in all cell lines tested, regardless of MET expression levels. Herein, we demonstrate that STAT3 functions as a common driver of tumourigenesis in multiple NF1-MPNST cell lines with varying signalling profiles. STAT3 is activated downstream of a variety of receptor tyrosine kinases which are associated with NF-1-tumourigenesis, including MET, IL-6 and EGFR, making it an appealing therapeutic target for the heterogeneous NF1-MPNST population. We also demonstrate that cellular migration, invasion and tumour formation through STAT3 is highly dependent on the transcription factor HIF-1α, where knockdown of HIF-1α ablated these oncogenic facets of STAT3. Our research demonstrates that aberrant signalling through STAT3 and HIF-1α drives tumour progression within MPNSTs, indicating that inhibition of the STAT3/HIF-1α /VEGF-A signalling axis could be a viable therapeutic strategy in this context.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit:	30 March 2016
Last Modified:	07 Mar 2022 16:48
URI:	https://orca.cardiff.ac.uk/id/eprint/87142

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