PhD Studentship: Investigating RUNX2 mRNA Structural Plasticity and Dysregulation in Fusion Positive Sarcomas

Primary supervisor - Dr Darrell Green

Paediatric cancer is the leading cause of childhood disease mortality. In contrast to adult cancers where exogenous mutagens or age accumulated DNA damage drives tumour development, childhood cancers lack the extended time frame needed to accumulate the mutations required for tumorigenesis by those routes. Therefore, endogenous mutagenic processes are a likely source for cancer enabling mutations in paediatric cancers. 

An important observation in humans indicating a developmental origin of paediatric cancer is in childhood acute lymphoblastic leukaemia, which evolves in two discrete steps. First, in utero initiation where fusion gene formation (ETV6::RUNX1) or hyperdiploidy generates a pre-leukemic clone. Second, in a small fraction of these cases and sometimes with a protracted latency (1-15 years), postnatal acquisition of secondary genetic changes (e.g. caused by infection) drives conversion to overt leukaemia.

Bone sarcoma (e.g. Ewing sarcoma, osteosarcoma) cell and time of origin is debated but experimental studies in different models suggest possible in utero induction with postnatal initiation similar to leukaemia. In Ewing sarcoma, FET::ETS gene fusions (most commonly EWSR1::FLI1) are generated either by balanced chromosomal translocations or a ‘burst’ of loop like rearrangements termed chromoplexy. The encoded fusion oncoproteins create de novo enhancers at repetitive GGAA DNA elements (GGAA microsatellites). These neo-enhancers appear to contribute to tumorigenesis and eventually tumour progression and possibly underlie germline variation.

The initiating secondary genetic changes causing overt clinical disease that progresses to metastasis remains unknown. Metastasis is thought to be independent to tumorigenesis. Metastasis is a highly complex multistep cascade of apparent serendipitous events performed with exquisite – but fatal - repeatability across patients with cancer. Drug resistant (and inoperable) metastases are the leading cause of cancer patient related death and therefore the leading clinical oncology challenge. Although the key driver mutations and some recurrent alterations have been reported in bone sarcomas (and muscle sarcomas such as rhabdomyosarcoma), fragmented data from multiple small series has hampered global elementary understanding of metastasis biology and - therefore – targeted therapy development. It remains unresolved – and is therefore a continued knowledge gap - whether bone and muscle sarcoma metastases evolve through linear Darwinian evolution, parallel progression, reversible/plastic mechanisms and/or whether a metastatic clone already exists at tumorigenesis and needs time to expand.

Cellular RNAs are heterogeneous with respect to their alternative processing, subcytoplasmic location and secondary (and hence tertiary) structures. The functional importance of this complexity is under explored. Our recent work indicates that different RNA isoforms adopt multiple distinct and functionally relevant structural conformations, independent of the RNA sequence, whose plasticity in abundance and shape has significant influence on transcriptional output and reprogramming of the transcriptome. We also showed (published and unpublished) that RUNX2 is a sarcoma associated gene involved in overt metastatic disease, and modulation of RUNX2 expression (e.g. through drug inhibitors) can plastically change cancer cell phenotype between bone and muscle cancer cells. This PhD studentship will combine multiple lines of enquiry/hypotheses to investigate RUNX2 RNA structure (plus microRNA and RBP binding) in different sarcomas and whether preclinical modulation of the mRNA structure can block metastatic progression. 

Entry requirements

The minimum entry requirement is 2:1 in biological sciences or similar.

Start date: 1 August 2025

Additional Funding Information

This PhD opportunity offers funding for 3 years and comprises of tuition fees at Home fee rates, a stipend of £19,367 and £1,000 per annum to support research training. 

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