Green Group

RNA silencing in paediatric cancer

Our Research in RNA Silencing in Paediatric Cancer

The origin of many paediatric cancers lies in aberrant human development. In contrast to adult cancers in which exogenous mutagens or age accumulated DNA damage drives tumour development, paediatric cancers lack the extended time frame required to accumulate the mutations required for tumorigenesis by these routes. Endogenous in utero mutagenic processes are a likely source for cancer inducing mutations in paediatric cancers. At the molecular cell level, paediatric tumours are generally characterised by terminal differentiation failure, epigenetic changes and gene rearrangements. Rearrangements caused by structural variants and gene fusions tend to have a more extensive transcriptional impact than point mutations; indeed, paediatric cancers comprise significantly more transcriptional diversity than adult tumours. In the Green lab, we use molecular techniques and computational approaches to investigate post-transcriptional gene regulation in paediatric sarcomas. Our work is intended to better understand gene regulatory mechanisms and sarcoma biology, which could lead to the development of new targeted therapies.

Group Leader: Dr Darrell Green
I 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.
View my research profile

Please get in touch regarding PhD research opportunities

Postgraduate Research Opportunities

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. tRNAGly^TCC) 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.

Fusion driven sarcomas

Ewing sarcoma (EwS) is characterised by gain-of-function gene fusions, usually EWSR1 fused to FLI1. Similarly, fusion-positive rhabdomyosarcoma (FP-RMS) is characterised by gene rearrangements between PAX3 or PAX7 with FOXO1. EwS cells exist in two reversible states driven by the fusion oncoprotein, EWSR1::FLI1. High expression promotes proliferation, while low expression enhances migration and metastasis. These high/low states have only been confirmed using signature analyses because the fusion is barely detectable at the mRNA level. As such, it could be that fusion mRNA levels do not change but its translation rate does. RNA is a single-stranded molecule, able to fold back on itself to form intricate secondary and tertiary structures. Gene expression requires the accurate assignment of specific RNA structures to individual transcript isoforms. RNA structure formation (and plasticity) is governed by the crosstalk between ions, macromolecular crowding, RNA-binding proteins (RBPs), and post-transcriptional modifications. These structures are crucial to the ability of RNA to perform complex biological functions such as catalysis, regulation of gene expression, and macromolecular scaffolding. We are investigating the causes and consequences of RNA structure dysregulation in EwS and FP-RMS. Rather than focusing on the oncoproteins, we aim to reveal novel RNA structural biology mediated mechanisms of metastasis that could lead to new therapeutic strategies.

CADD522

Paediatric sarcomas (e.g. Ewing sarcoma, osteosarcoma, rhabdomyosarcoma) are treated using chemotherapy and surgery but morbidity is high, and survival rates remain low. Targeted therapies that are more effective and less toxic are needed. RUNX2 is a transcription factor essential for in utero development. We discovered RUNX2 “reactivation” and its role as an oncogenic transcription factor in paediatric sarcomas. Transcription factors including RUNX2 are difficult to target therapeutically because they do not contain a well-defined binding site typically found in other “druggable” 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 sarcoma, CADD522 demonstrated potent anti-cancer efficacy suppressing RUNX2 target gene transcription. CADD522 significantly increased progression-free and overall survival with no apparent side effects.

Recent Publications