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Our Research
Cancer is the leading cause of death by disease in children and young adults. A major reason is the intrinsic ability of some paediatric cancers to become resistant and relapse, even after an initially successful response. Once relapse occurs, therapeutic options are scarce, and survival rates remain dismal. Unlike adult cancers, paediatric tumours harbour few mutations, suggesting they evolve through cellular plasticity rather than genetic diversification. Arising during development from inherently plastic cells, they retain the ability to switch phenotypes without altering DNA, enabling rapid, reversible transitions into metastatic and drug-tolerant states. The Green Lab applies molecular and bioinformatic approaches, including machine learning and AI, to investigate such non-genetic plasticity in paediatric cancer, aiming to identify new therapeutic targets.
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Group Leader: Dr Darrell Green
View my research profileI am the scientific group leader for RNA research at Norwich Medical School. I first trained as a biomedical scientist at Addenbrooke’s Hospital in Cambridge before completing my PhD at the University of East Anglia with a focus on microRNA and bone cancer. I undertook postdoctoral training at UEA expanding on this work, developing single-cell RNA sequencing in circulating tumour cells, before setting up my own group in 2018.
Please get in touch regarding PhD research opportunities
THE BIOLOGY OF BONE SARCOMAS
While primary tumour analyses have illuminated mechanisms of tumorigenesis, fatal metastases remain poorly understood. We have a long-standing research interest in the role of small RNAs in metastasis, building on training in a laboratory that identified key components of the RNAi and microRNA pathways. Early work identified oncogenic roles for microRNAs (e.g. miR-140) and tumour suppressor roles for tRNA-derived fragments (e.g. tRNAGlyTCC), and their interactions with RNA-binding proteins (e.g. YBX1). We developed new techniques to investigate circulating tumour cells, i.e. metastatic precursors, at single-cell resolution, which provided some of the earliest direct experimental evidence of non-genetic phenotypic plasticity during metastasis (e.g. mediated by MAPK7). More recently, we have discovered that metastatic cells can generate non-coding RNAs not observed in normal or even tumour cells, accessing their so-called “dark genome” to enable disease spread.
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RNA STRUCTURE IN FUSION ONCOGENE REGULATION
Ewing sarcoma (EwS) is driven by gain-of-function FET::ETS gene fusions, most commonly EWSR1::FLI1, encoding a pioneer transcription factor that creates de novo enhancers at repetitive GGAA DNA microsatellites. The EWSR1::FLI1 oncoprotein governs two reversible cellular states, a proliferative “high” state and a migratory “low” state. These phenotypes have been inferred from gene signatures because the fusion mRNA transcript is often barely detectable, suggesting regulation may occur at the translational or structural RNA level. RNA folding, shaped by ions, RNA-binding proteins and post-transcriptional modifications, underpins transcript stability and function. Our work investigates how aberrant RNA structure, and its regulation contributes to metastasis in EwS, aiming to uncover RNA-mediated mechanisms that could be exploited therapeutically.
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UEA-522 DRUG DEVELOPMENT
Paediatric sarcomas remain largely incurable following metastasis to the lungs and/or bone marrow, driven in part by cancer cell plasticity and chemotherapy resistance. Improving outcomes therefore requires strategies that constrain metastatic plasticity rather than further intensifying cytotoxic regimens. Through our work on miR-140, we identified RUNX2 as a master regulator of this plasticity. While distal P1-driven RUNX2 controls osteoblast and chondrocyte differentiation, proximal P2-driven RUNX2, lacking exons 1 and 2, regulates mesenchymal lineage decisions, sustains proliferation, and suppresses apoptosis and terminal differentiation. As transcription factors lack conventional drug-binding pockets, computer-aided drug design was used to develop CADD522, now UEA-522, a small-molecule inhibitor of RUNX2 transcriptional activity. Preclinically, UEA-522 potently suppressed RUNX2 target genes and significantly improved metastasis-free and overall survival without overt toxicity. We are now advancing UEA-522 towards first-in-human readiness.
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Recent Publications
Multi-modal therapeutic action of gallium-containing bioactive glass against osteosarcoma and bacterial pathogens
de Souza et al. (2026) – Engineered RegenerationTargeting metastasis in paediatric bone sarcomas
Bull et al. (2025) – Molecular CancerBayesian unsupervised clustering identifies clinically relevant osteosarcoma subtypes
Llaneza-Lago et al. (2024) - Briefings in Bioinformatics
Green et al. (2024) – Clinical Cancer Research
YBX1-interacting small RNAs and RUNX2 can be blocked in primary bone cancer using CADD522
Green et al. (2023) – Journal of Bone Oncology Rated Most Popular Paper in JBO 2023-2026