About the Project
Soft tissue sarcomas are a heterogenous group of mesenchymal tumours that can resemble tissues or appear undifferentiated. Synovial sarcomas are a type of sarcoma that have a pluripotent ability to differentiate into many cell types of mesenchymal origin and can even have an epithelial/glandular component. They frequently arise in joints, affect mainly young adults and when metastatic survival rates are <50%. New more effective, targeted, less toxic therapies are required for patients with synovial sarcomas.
All synovial sarcomas are associated with chromosome translocations that fuse SS18 and SSX genes that produce an aberrant fusion protein. The SS18-SSX fusion protein re-programmes cells through gene expression changes and associated epigenetic changes. The function of the SS18-SSX fusion protein has been shown to involve the SWI/SNF (BAF) and polycomb chromatin remodeling complexes in maintaining the stem cell-like properties of synovial sarcomas. Epigenetic changes include histone modifications, such as methylation, can alter chromatin conformation, gene transcription, DNA repair and genetic stability. Histone methylation is a tightly regulated process in normal cellular development and differentiation and its deregulation can significantly influence the malignant progression of cancers, although this is not well understood for synovial sarcomas. The genes encoding the enzymes that add or remove methyl groups from histone tails are known as histone methyltransferases and demethylases, respectively, and are emerging as promising therapeutic targets.
Our preliminary data strongly supports involvement of histone demethylases in the malignant behaviour of synovial sarcomas and we hypothesize that this is related to the activity of the fusion protein. The overall aim of this studentship project is to identify and determine how therapeutically targetable histone demethylase enzymes play a role in the malignant phenotype of synovial sarcomas.
The more specific aims are to:
• Identify which histone demethylases impact most on growth and viability of synovial sarcoma cells and assess whether this is dependant on the oncogenic SS18-SSX fusion protein associated with synovial sarcomas.
• Determine the molecular mechanisms underlying the activity of histone demethylase(s) in synovial sarcoma.
• Provide pre-clinical evidence to support use of histone demethylase inhibitors in the treatment of synovial sarcomas.
Investigations will include developing and using models of synovial sarcomas alongside molecular biology techniques to modulate and assess gene expression and phenotypic changes to cells. Co-immunoprecipitation (coIP) will be used to demonstrate protein interactions with previously described and/or novel complexes. These approaches will determine the genes affected by the histone demethylase, the methyl marks involved and the interacting proteins in order to develop a mechanistic molecular model of how the histone modifier interacts to affect malignant behaviour of synovial sarcomas. Synovial sarcoma models will be tested for their sensitivities to available histone demethylase inhibitors/tool compounds, including combining with existing chemotherapy to assess potential for introduction into patients. Promising results will be taken forward for in vivo studies.
Together, this project offers the potential to discover epigenetic mechanisms that contribute to the malignant phenotype of synovial sarcomas that could lead to improved treatment for patients with synovial sarcomas. It is also expected to develop skills and expertise in molecular, epigenetic and cellular techniques and abilities to interpret and present data from experiments in the context of current understanding. This will take place in an interactive, collaborative and supportive team and institutional environment.
https://www.icr.ac.uk/our-research/research-divisions/division-of-molecular-pathology
Download a PDF of the complete project proposal: https://d1ijoxngr27nfi.cloudfront.net/docs/default-source/studying-at-the-icr/7_shipley_selfe_houlston_icr-studentship.pdf?sfvrsn=65eb5e69_2
Candidate profile
Candidates must have a first class or upper second class honours BSc Honours/MSc in relevant Biological Science.
How to apply
Full details about these studentship projects, and the online application form, are available on our website, at: www.icr.ac.uk/phds Applications for all projects should be made online. Please ensure that you read and follow the application instructions very carefully.
Closing date: Monday 19th November 2018
Applicants should be available for interview 28h and 29th January 2019.
Please apply via the ICR vacancies web portal
https://apply.icr.ac.uk/
References
Stacchiotti S, Van Tine BA. (2018) Synovial Sarcoma: Current Concepts and Future Perspectives. J Clin Oncol. 36(2), 180-187.
Naka N, Takenaka S, Araki N, Miwa T, Hashimoto N, Yoshioka K, Joyama S, Hamada K, Tsukamoto Y, Tomita Y, Ueda T, Yoshikawa H, Itoh K. (2010). Synovial sarcoma is a stem cell malignancy. Stem Cells. 28(7), 1119-1131.
Jones S, Fleuren E, Frankum J, Konde A, Williamson C, Krastev D, Pemberton H, Campbell J, Gulati A, Elliott R, Menon M, Selfe J, Brough R, Pettitt S, Niedzwiedz W, van der Graaf W, Shipley J*, Ashworth A*, Lord C* (*joint). (2017). ATR is a therapeutic target in synovial sarcoma. Cancer Res. 77(24), 7014-7026.
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