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Our research in RNA silencing in cancer
The Green lab uses molecular techniques and computational approaches to study RNA-based gene silencing. Our research is a mix of basic and translational with projects ranging from fundamental mechanisms to drug development. Our primary interests are in bone and soft tissue tumours, which predominantly affect children, teenagers and young adults. Our work is intended to better understand the biology of sarcomas, leading to improved and targeted therapies.
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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.
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Bone Tumours
Drug resistant metastases are the leading cause of cancer-related death. Our research started with studying the molecular biology that underpins metastasis, which is independent to tumorigenesis. Early work looked at the role of small RNAs in cancer evolution and identified pro-tumoral roles for microRNAs (e.g. miR-140) and tumour suppressor roles for tRNA-derived fragments (e.g. tRNAGlyTCC) plus their interactions with RNA-binding proteins (e.g. YBX1). More recently we have focused specifically on circulating tumour cells, i.e. the “seeds” of metastasis, and their fundamental biology at single-cell resolution, which drives the spread of cancer around the body. We identified novel gene networks (e.g. MAPK7/MMP9) that enable metastatic cells to inappropriately interact with tumour-associated macrophages causing metastasis. We also discovered that metastatic cells are able to produce non-coding RNAs not observed in normal or even tumour cells; accessing the ‘dark matter’ of their genomes to enable disease spread.
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Fusion-positive sarcomas
Ewing sarcoma (EWS) is characterised by gain-of-function gene fusions between FET (FUS, EWSR1, TAF15) RNA-binding proteins and ETS (FLI1, ERG, FEV) transcription factors. Most EWS patients (>85%) share the same driver in which EWSR1 is fused to FLI1. Similarly, fusion-positive rhabdomyosarcoma (FPRMS) is characterised by gain-of-function gene rearrangements between PAX3/7 and FOXO1. Unlike many other cancers, there is a notable paucity of other somatic and epigenetic alterations in EWS and FPRMS. Despite the relatively simple genetic architecture, the manifestation of these cancers in patients is clinically heterogeneous. Cellular RNAs including those from the EWSR1::FLI1 and PAX3/7::FOXO1 fusions are heterogeneous with respect to their alternative processing, subcytoplasmic location and secondary (and hence tertiary) structures. We are investigating the functional importance of the three-dimensional structures of the fusion mRNAs. It is proposed 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.
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CADD522
Bone sarcomas (e.g. Ewing sarcoma, osteosarcoma) are treated using non-specific chemotherapy but morbidity is high and survival rates remain low. Targeted therapies that improve patient outcomes are needed. RUNX2 is a transcription factor essential for embryonic osteoblastic differentiation and skeletal morphogenesis. We uncovered RUNX2 as an oncogenic transcription factor in bone cancer. Transcription factors including RUNX2 are difficult to target therapeutically because they do not contain a well-defined binding site typically found in other macromolecules such as enzymes. With our collaborators, using computer-aided drug design (CADD), we developed the lead compound CADD522, a small molecule inhibitor of RUNX2 DNA-binding. In orthotopic xenograft mouse models of bone sarcomas, CADD522 demonstrated potent efficacy suppressing RUNX2 target gene transcription. CADD522 significantly increased metastasis-free and overall survival with no apparent side effects.
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Recent Publications
Biological Sample Collection to Advance Research and Treatment: A Fight Osteosarcoma Through European Research and Euro Ewing Consortium Statement
View the publication onlineGreen et al. (2024) – Clinical Cancer Research
YBX1-interacting small RNAs and RUNX2 can be blocked in primary bone cancer using CADD522
View the publication onlineGreen et al. (2023) – Journal of Bone Oncology
3' Untranslated Region Structural Elements in CYP24A1 Are Associated With Infantile Hypercalcemia Type 1
View the publication onlineBall et al. (2023) – Journal of Bone and Mineral Research
Mechanistic insights into non-coding Y RNA processing
View the publication onlineBillmeier et al. (2022) – RNA Biology
Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer
View the publication onlineGreen et al. (2020) – Oncogene