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Item Exploring the mechanisms of phenotypic plasticity in paediatric cancer: investigating the role of transcriptional noise and developing evolving barcoding approaches(Institute of Cancer Research (University Of London), 2026-02-13)Despite its relatively low genetic variability, neuroblastoma is characterised by at least two distinct cell identities: proliferative adrenergic and therapy-resistant mesenchymal cells. Transitions between these states have been observed, but the mechanisms driving such phenotypic plasticity remain poorly understood. Here, we propose that transcriptional noise – the stochastic variability in gene expression arising from the discontinuous nature of transcription – acts as a key regulator of plasticity. Using transcriptional, phenotypic and functional assays in neuroblastoma and hepatoblastoma models, we show that induction of transcriptional noise promotes phenotypic plasticity. Cells undergoing transitions, whether at baseline or during awakening after treatment, display increased noise particularly in regulators of cell identity. Importantly, inhibition of KDM5 demethylases after cisplatin exposure reduces noise and halts plasticity-driven awakening and regrowth. Our findings support a model in which transcriptional noise destabilises cell-identity networks, enabling stochastic transitions between states. This establishes transcriptional noise as both a mechanistic driver of plasticity and a potential therapeutic vulnerability to prevent relapse. To extend these findings, we applied evolving DNA barcodes and identified additional candidate regulators of plasticity as well as developed PMRec, a molecular recording platform designed to couple lineage tracking with cell-state information. These tools provide unprecedented resolution for studying plasticity events and lay the groundwork for future studies into the dynamics of adaptation in paediatric cancers.
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