Oncostatin M Receptor Overexpression Promotes Tumour Progression in Squamous Cell Carcinoma, via Hypoxia Signalling and Multiple Effects on the Tumour Microenvironment

Cervical cancer still represents the fourth most common cause of cancer deaths in women worldwide. Human papilloma virus (HPV) infection plays a role in cervical carcinoma initiation, but other genomic changes are needed for pre-malignant abnormalities to fully develop to cancer. This often happens through genomic instability caused by the virus oncoproteins. Several integrative genomic analysis studies have found that one of the most common imbalances in cervical squamous cell carcinoma (SCC) is copy number gain and amplification of chromosome 5p. In this region, copy number gain of the OSMR gene was found to correlate significantly with adverse outcome independent of the tumour stage (p=0.046). Furthermore, this copy number gain correlated with Oncostatin M receptor (OSMR) overexpression and sensitised these cells to Oncostatin M (OSM) leading to increased Signal transducer and activator of transcription 3 (STAT3) phosphorylation, cell migration, invasion and proangiogenic signalling. The aim of this PhD project was to study the role of OSMR overexpression in the SCC tumour microenvironment (TME) and tumour growth in vivo and to study the role of hypoxia inducible factor driven hypoxia signalling in OSMR overexpressing SCC cells and their tumour microenvironment. OSMR overexpression was found to sensitise tumour cells to induce Hypoxia inducible factor 1a and 2a (HIF1a, HIF2a) signalling in normoxic conditions, to promote pro-angiogenic signalling. Furthermore, hypoxic conditions were found to enhance OSM signalling in OSMR overexpressing cells leading to increased expression of markers of epithelial to mesenchymal transition, angiogenesis and migration. In the SCC tumour microenvironment, OSMR overexpression was found to sensitise tumour cells to OSM secreted from macrophages and other immune cells leading to improved tumour growth, angiogenesis and STAT3 activation at the tumour site. Removal of OSMR from either tumour cells or tumour microenvironment led to reduced tumour growth and angiogenesis, along with increased tumour necrosis. I conclude that OSMR overexpression is an important driver of SCC tumour progression and malignancy via STAT3- and HIF-driven signalling and removal of it from either tumour cells or tumour microenvironment drastically hampers tumour growth in vivo. Based on the results of this study, OSMR blockade is a potential novel therapeutic option in advanced SCC.Departmental scholarshi

Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial-mesenchymal transition and poor overall survival.

BACKGROUND: Copy-number gain of the oncostatin-M receptor (OSMR) occurs frequently in cervical squamous cell carcinoma (SCC) and is associated with adverse clinical outcome. We previously showed that OSMR overexpression renders cervical SCC cells more sensitive to the major ligand oncostatin-M (OSM), which increases migration and invasion in vitro. We hypothesised that a major contribution to this phenotype would come from epithelial-mesenchymal transition (EMT). METHODS: We performed a comprehensive integrated study, involving in vitro cell line studies, in vivo animal models and numerous clinical samples from a variety of anatomical sites. RESULTS: In independent sets of cervical, head/neck and lung SCC tissues, OSMR expression levels correlated with multiple EMT-associated phenotypic markers and transcription factors. OSM treatment of OSMR overexpressing cervical SCC cells produced consistent EMT changes and increased tumour sphere formation in suspension culture. In a mouse model, OSMR overexpressing SCC cells treated with OSM showed significant increases in lung colonisation. The biological effects of exogenous OSM were mirrored by highly significant adverse overall survival in cervical SCCs with OSMR overexpression (N=251). CONCLUSIONS: OSM:OSMR interactions are able to induce EMT, increased cancer stem cell-like properties and enhanced lung colonisation in SCC cells. These changes are likely to contribute to the highly significant adverse outcome associated with OSMR overexpression in cervical SCCs.This work was supported by Cancer Research UK (Programme Grant A13080).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group

Mitochondrial myopathy induces a starvation-like response

niversity on Septem ber 12, 201