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Title: Effects of oncostatin-M receptor overexpression on cervical squamous cell carcinoma cells and their extracellular vesicles
Author: Trendell, Jennifer
ISNI:       0000 0004 9348 1893
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Cervical carcinoma remains the fourth most common cause of cancer in women worldwide. Cytological screening and introduction of prophylactic HPV vaccines have drastically decreased incidence rates in high income countries. However, it is still one of the leading causes of cancer morbidity in middle and low income countries and the prognosis for advanced or recurrent cervical carcinoma remains poor. Further research to enhance the current understanding of molecular aberrations driving cervical carcinoma is, therefore, vital in order to develop effective novel therapies. The oncostatin-M receptor (OSMR) frequently undergoes copy-number gain and overexpression in squamous cell carcinomas (SCC) at multiple sites, consistently associated with an adverse overall survival independent of tumour stage. OSM-OSMR signalling activates STAT3 and MAP-kinase pathways and induces a pro-malignant phenotype including increased cell migration, invasion and angiogenesis. Bidirectional communication between cancer cells and cells of the tumour microenvironment (TME) is essential for tumour progression. There is mounting evidence to suggest that extracellular vesicles (EVs) are key mediators of intercellular communication and can promote tumour progression through various mechanisms. The work presented in this PhD thesis aims to determine the effect of OSM-OSMR signalling on mRNA and miRNA expression in cervical SCC cells and their extracellular vesicles. Next generation sequencing (NGS) was used to investigate global changes in mRNA and miRNA expression. These experiments were performed using SW756 cells, a cervical SCC cell line with OSMR copy number gain and overexpression, and an OSMR knock down (KD) SW756 cell line generated by CRISPR-Cas9. OSM-OSMR signalling was found to be capable of modulating both cellular and EV mRNA expression. Treatment of SW756 cells with OSM resulted in significant (p≤0.01) upregulation of 225 (cell) and 88 (EV) mRNAs and downregulation of 98 (cell) and 202 (EV) mRNAs. Treatment of SW756 OSMR KD cells with OSM resulted in no significant changes in cellular or EV mRNA expression. Pathway analysis revealed that genes primarily involved in cytokine mediated signalling, hypoxia response, interferon response and negative regulation of viral lifecycle, myeloid leukocyte activation and angiogenesis were all upregulated in response to OSM, whereas, genes involved in cell cycle regulation, cellular organisation and cell differentiation were downregulated. Effects of OSM-OSMR signalling on cellular and EV miRNA expression was found to be less pronounced. The effect of OSM-OSMR signalling on tumour growth in vivo was also investigated. OSMR KD cells had a reduced growth rate following sub-cutaneous transplantation in NOD-SCID mice, compared with SW756 cells. Similarly, SW756 cells with constitutive-overexpression of OSM grew more quickly than SW756 in vivo. Together, this work indicates that OSM-OSMR signalling is an important driver of cervical SCC tumour progression both in vitro and in vivo, and demonstrates, for the first time, that OSM-OSMR signalling alters EV composition in cervical SCC cells. Subsequent work will focus on elucidating the functional importance of these EVs and their effects on cells of the TME.
Supervisor: Coleman, Nicholas Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: cancer ; cervical cancer ; Onctostatin-M Receptor ; extracellular vesicles ; microRNA ; Tumour microenvironment ; in vivo model