Green Group

While primary tumour analyses have illuminated mechanisms of tumorigenesis, fatal metastases remain poorly understood. Our research started with studying the molecular biology that underpins metastasis. Early work looked at the role of small RNAs in disease progression and identified oncogenic roles for microRNAs (e.g. miR-140) and tumour suppressor roles for tRNA-derived fragments (e.g. tRNAGly^TCC), and their interactions with RNA-binding proteins (e.g. YBX1). We developed new techniques to investigate circulating tumour cells, i.e. the “seeds” of metastasis,  and their fundamental biology at single-cell resolution. This work identified gene regulatory networks (e.g. MAPK7 and MMP9) that dictate tumour-immune interaction and metastatic outcome. More recently, we have discovered that metastatic cells can generate functional non-coding RNAs not observed in normal or even tumour cells, accessing their so-called “dark genome” to enable disease spread.

Paediatric sarcomas that metastasise to the lungs and/or bone marrow have poor outcomes and remain largely incurable, mainly because sarcoma cell plasticity drives chemotherapy resistance. Improving outcomes therefore requires strategies that prevent or impede metastatic plasticity, rather than further intensifying cytotoxic regimens. We identified the transcription factor RUNX2, classically known for controlling osteoblast and chondrocyte differentiation from its distal P1 promoter, as a master regulator of sarcoma plasticity. RUNX2 from its proximal P2 promotor, lacking exons 1 and 2, shapes mesenchymal lineage decisions, maintains proliferation, and suppresses apoptosis and terminal differentiation. As transcription factors lack conventional drug-binding pockets, we used computer-aided drug design to develop UEA-522, a small molecule inhibitor that blocks RUNX2-DNA binding. In preclinical studies, UEA-522 potently suppressed RUNX2 target gene expression and significantly improved metastasis-free and overall survival with no detectable side effects. We are now advancing UEA-522 towards first-in-human readiness.