iRHOM2 in oesophageal squamous cell cancer

Cancer Research UK PhD studentship
Centre for Cell Biology and Cutaneous Research
Blizard Institute
Barts and the London School of Medicine
Queen Mary University of London

Project Title: iRHOM2 in oesophageal squamous cell cancer

Supervisor: Prof. David Kelsell
Co-Supervisor: Prof. Andrew Silver

Applications are sought for this 4 year studentship funded by a Cancer Research UK programme grant working on the role of the recently discovered oesophageal cancer susceptibility gene iRHOM2. An enthusiastic graduate with an interest in Cancer Cell Biology and Human Genetics and with at least an upper second class honours degree is required for this project based at the Centre for Cell Biology and Cutaneous Research located at the Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, to commence in October 2015
.
The aim of this project is to investigate the role of iRHOM2 in oesophageal squamous cell carcinoma (OSCC). Recently, we identified iRHOM2 mutations associated with the dominant cutaneous and oesophageal cancer-susceptibility syndrome Tylosis; this is the first highly penetrant gene mutation for OSCC susceptibility (Blaydon et al, 2012). Furthermore, we have shown that iRHOM2 mutations cause an increase in the maturation and activity of ADAM17 in keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. Thus, the iRHOM2-ADAM17-EGFR axis has a critical role in epithelial barrier formation, repair and inflammation (Brooke et al, 2014). Inflammation and dysregulation of the EGFR pathway predisposes to many cancers including OSCCs. This studentship will utilise a number of genetic, molecular and cell biological techniques to investigate further the role of iRHOM2 in normal and cancer keratinocyte biology.
The student will be an integral part of a newly awarded Cancer Research UK programme grant to Professor David Kelsell and co-applicants: Prof Andrew Silver (Blizard), Dr Janet Risk (University of Liverpool) and Prof Rebecca Fitzgerald (University of Cambridge). Additionally, the student will interact closely with members of the Centre for Cell Biology and Cuatenous Research and other researchers within the Blizard Institutes.
Our laboratory is located in the Blizard Institute located in Whitechapel. Here, the graduate will have access to a wide variety of cutting-edge technologies and core facilities, as well as interaction with researchers across a wide range of biomedical research. Barts and The London School of Medicine was ranked 7th in the UK for research in Clinical Medicine in the most recent Research Excellence Framework (REF) 2014.

Relevant references:
Matthew A. Brooke, Sarah L. Etheridge, Nihal Kaplan, Charlotte Simpson, Edel O’Toole, Akemi Ishida-Yamamoto, Olivier Marches, Spiro Getsios, David P. Kelsell (2014). iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function. Human Molecular Genetics 1;23(15):4064-76.

Diana C. Blaydon, Sarah L. Etheridge, Janet M. Risk, Hans-Christian Hennies, Laura Gay, Vincent Plagnol, Fiona McRonald, Howard P. Stevens, Nigel K. Spurr, D. Timothy Bishop, Anthony Ellis, Janusz Jankowski, John K. Field, Irene M. Leigh, Andrew P. South, David P. Kelsell (2012). RHBDF2 mutations are associated with a familial esophageal cancer syndrome (Tylosis). American Journal of Human Genetics. 10;90(2):340-6.

Diana C. Blaydon, Paolo Biancheri, Wei-Li Di, Vincent Plagnol, Rita M. Cabral, Matthew A. Brooke, David A. van Heel, Franz Ruschendorf, Mark Toynbee, Amanda Walne, Edel A. O’Toole, Joanne E. Martin, Keith Lindley, Tom Vulliamy, Dominic J. Abrams, Thomas T. MacDonald, John I. Harper, David P. Kelsell (2011). Neonatal-onset inflammatory skin and bowel disease associated with a recessive loss-of- function mutation in ADAM17. New England Journal of Medicine. 365(16):1502-8.


For an informal discussion, please contact the lead project supervisor:
Prof David Kelsell Email: [Email Address Removed]