Childhood cancers remain the leading cause of disease-related death in young people partly because many tumours become treatment-resistant and relapse. Unlike adult cancers, paediatric tumours carry very few genetic mutations. Instead, they rely on cellular plasticity – the ability to rapidly and reversibly change their behaviour without altering DNA – to survive therapy. This allows cancer cells to enter drug-tolerant, dormant states (“playing dead”) and later reawaken to drive relapse, a process missed by standard genetic tests.
This idea draws on long-standing evolutionary theories, including plasticity-first evolution (Baldwin effect), where organisms adapt through phenotypic shifts before genetic changes occur. Recent work in lava-dwelling lizards has demonstrated this phenomenon in nature.
In cancer, similar adaptive processes happen on extremely fast timescales. However, studying them has been challenging because existing tools capture only static snapshots of cell states. To overcome this, Alejandra Bruna’s team has developed a molecular recorder that tracks real-time phenotypic transitions and lineage histories, revealing that only some childhood cancer cells are highly plastic, with epigenetic regulation—such as chromatin rewiring and histone modifiers like KDM5—shaping their ability to switch states.
The long-term goal is to translate this understanding into the clinic: developing early warning systems for treatment adaptation and designing anti-plasticity therapies that block or prevent state switching. By learning to read and control non-genetic evolution, researchers aim to stop relapse before it starts and improve outcomes for children with cancer.
Credit: Dr Alejandra Bruna | Cancer Research UK