Clinical Translational Study on Cancer Exosomes

MRC PhD Studentship
Centre for Clinical & Diagnostic Oral Science
Institute of Dentistry
Barts and the London School of Medicine & Dentistry
Queen Mary University of London

Academic supervisors: Dr Muy-Teck Teh and Dr Catherine Harwood

Project Title: Clinical Translational Study on Cancer Exosomes

Applications are invited from graduates with a BSc (First or Upper Second) or MSc (Distinction). Previous research experience would be an advantage. This 3 year studentship will commence on 1st October 2015 and the applicant will be based in the School's Whitechapel Campus. This is an exciting opportunity for a graduate from disciplines related to cell and molecular biology, cancer biology, clinical translation, biotechnology and biomedical science.

Background:
Exosomes are nanoparticles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. They are spherical bilayered membrane proteolipids harbouring specific proteins and nucleic acid cargos. Non-coding RNA (microRNA, siRNA and piRNA) and mRNA are key cargos of exosomes. Their key function being intercellular communication with both neighbouring as well as distant cells. It has been suggested that tumour cells exploit this intercellular communication mechanism to confer target cell reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis. Our pilot study found that the oncogene FOXM1 (Teh et al., 2013, Int J Cancer, 132(9):2095-106; Gemenetzidis et al., 2010, Cancer Res., 70(22):9515-26; Teh, 2012, Front Oncol., 2:146) was enriched in exosomes secreted from a cancer cell line. We therefore hypothesised that exosomal FOXM1 may play a role in oncogenic reprogramming and distant metastasis.

Clinical Translation
Head and neck squamous cell carcinoma (HNSCC) is diagnosed in over half a million individuals worldwide each year, with an expected global incidence of 750,000 by 2015. According to the 8th national annual head and neck cancer audit report published by UK Health and Social Care Information Centre, there were 8272 cases within the England and Wales in 2012. Survival rates are poor (10-30% at five years) among patients presenting with advanced disease. Early detection of precancer lesions coupled with early intervention could significantly improve patient outcome, reduce mortality and alleviate healthcare costs. Unfortunately, conventional histopathology is not able to identify which of the potentially malignant disorders (leukoplakia, actinic keratosis, lichen planus, etc) will transform to cancer. Given similar pathogenesis of other epithelial SCCs, the same clinical dilemmas apply to the management of skin premalignancies, an area of particular importance given the high prevalence of these premalignancies and the rapidly increasing incidence of cutaneous SCC. Hence, there is an urgent clinical need to explore novel methods for epithelial premalignant risk stratification. This study therefore aims to investigate the exosomal mechanism in oncogenic transformation using well characterised premalignant and malignant SCC cell lines and clinical specimens. Identification of oncogenes within exosomes represents a promising new avenue for developing a non-invasive cancer screening tool using saliva or blood.

Research Environment
The student will join a thriving group of at least 10 PhD students and 10 research-active staff members with diverse and interdisciplinary expertise working in our laboratory (Centre for Clinical & Diagnostic Oral Sciences, Institute of Dentistry) housed within the state-of-the-art Blizard Institute at Whitechapel. The Blizard Building provides a large interactive laboratory which facilitates interdisciplinary research and is an excellent environment for research training. This unique research environment brings together a critical mass of clinical and non-clinical scientists researching the cellular and molecular basis of diseases. The Institute of Dentistry, ranked 1st in the UK for Dentistry in the Complete University Guide 2015, has established the largest Head and Neck Cancer Research Group in the UK, and has been an area of major investment for the Institute.

Techniques
The supervisors can provide training on a wide range of well-established research methods including tissue culture of primary human keratinocytes, cancer cell lines, lipophilic gene transfection; retroviral transduction of exogenous genes or RNA interference constructs (short hairpin RNA); DNA, RNA and protein extraction from clinical biopsy specimens; reverse transcription PCR; real-time quantitative PCR; molecular gene cloning; Western Blotting; immunocytochemistry; live-cell fluorescence imaging; promoter/gene-reporter assays; organotypical culture on de-epidermalised dermis, gene cloning, next-generation sequencing, expression microarray meta-analysis and bioinformatics.

Informal Enquiries can be made to: Dr Muy-Teck Teh, e-mail: [Email Address Removed]