PhD Studentship: The Role of RNA Structure in Ewing Sarcoma

Ewing sarcoma (EWS) is the second commonest childhood bone cancer affecting ~2 per million individuals annually globally. One in three cases present with detectable pulmonary metastases. Standard of care following the Euro Ewing 2012 trial, which compared European and U.S. treatment protocols and then set an internationally aligned treatment guideline, comprises four months of non-specific combination chemotherapy, major surgery plus another four months of chemotherapy. Five-year survival is poor at ~50%, which is significantly below the combined childhood cancer five-year survival rate of 84% (UK), 81% (Europe) and 85% (U.S.). EWS is therefore a cancer of unmet need where better understanding and treatment improvements will disseminate internationally. Most EWS patients (>95%) share the same driver mutation (EWSR1::ETS) occurring within a genetic background characterised by few other recurrent cooperating mutations. Despite this simple genetic architecture, EWS is clinically heterogeneous. It remains entirely unclear why there is such clinical variability occurring from a common genetic aberration. Cellular RNAs including EWSR1::ETS are heterogeneous with respect to their alternative processing and secondary structure (analogous to protein tertiary structure), but the functional importance of this complexity at RNA level is poorly understood. Our research group/collaborators reported an RNA structure profiling method to determine the in vivo structure of single RNA molecules rather than the RNA population average. This work revealed that different RNA isoforms adopt multiple distinct and functionally relevant structural conformations that change in abundance and shape to influence transcriptional output. This PhD studentship will interrogate the RNA structurome of EWS. EWSR1::ETS fusion mRNA structure will be analysed in orthotopic xenograft and PDX mouse models and clinical samples at bulk and at single-cell resolution. RNA isoforms will be linked with the clinical phenotype and molecular mechanisms (e.g. microRNA binding, RNA binding protein interaction, RNA decay, etc.) investigated.

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Entry Requirements: Acceptable first degrees: Biological Sciences, Molecular Genetics, Molecular Biology and Biochemistry. Masters is required.

Funding

This 3-year PhD project is fully funded by the Richard Jenner Memorial Fund. Funding includes tuition fees (Home-fee rate), an annual stipend (£18,622 per annum, 2023/24 rate) and £1,000 per annual to support research training.

Directly Funded Project (UK Students Only)

Primary Supervisor: Dr Darrell Green

Start date: 1^st February 2024.

For more information on this project, please visit www.uea.ac.uk

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