83 In a new study, researchers have identified a critical link between serotonin and tumour growth in paediatric ependymomas, a rare and aggressive form of brain cancer in children. The study, published in Nature, reveals that serotonin – commonly associated with mood regulation – directly influences tumour progression through its role as an epigenetic marker on histones, proteins that package DNA and control gene expression. This discovery opens new potential avenues for targeted treatments aimed at halting tumour growth by modulating serotonin pathways. Ependymomas, particularly those driven by the ZFTA–RELA (ZRFUS) gene fusion, are known for their resilience to conventional therapies, such as chemotherapy, and often result in poor survival outcomes for young patients. Scientists have long suspected that ependymomas’ aggressive nature stems from unique epigenetic alterations, which affect gene expression without changing the underlying DNA sequence. In this recent study, researchers explored how serotonin is integrated into histones within these tumours, influencing cellular behaviour and tumour growth. Their findings mark the first evidence that serotonin operates as an “activating modification” on histones within brain tumour cells. The team examined the serotonylation of histones—the addition of serotonin molecules to histones—and found that this process was prevalent in ependymoma cells. This serotonylation appeared to drive tumour progression by enhancing the activity of specific transcription factors, proteins that regulate gene expression. By blocking histone serotonylation, researchers successfully inhibited tumour growth in mouse models. These findings underscore the pivotal role of serotonin not just as a neurotransmitter but as a driver of malignant growth in paediatric brain cancers. One of the study’s most striking results involves the identification of ETV5, a transcription factor activated by serotonylation. ETV5 was found to suppress the gene expression of Neuropeptide Y (NPY), a protein associated with tumour suppression. When ETV5 was active, NPY levels decreased, allowing tumours to grow unchecked. However, by artificially elevating NPY levels, researchers observed a reduction in tumour activity, as NPY’s overexpression helped to curb brain hyperactivity associated with tumour growth. The findings introduce serotonin as a dual-action molecule in the brain: while serotonin generally supports well-being in the brain’s normal cellular environment, it paradoxically appears to promote tumour development in ependymomas. The study suggests that modifying serotonin’s impact on tumour cells could serve as a novel therapeutic approach, potentially involving the use of serotonin inhibitors or treatments that counteract histone serotonylation in targeted cells. This discovery represents a significant step towards understanding how brain tumours hijack neurotransmitter systems to advance their growth. For families and young patients facing ependymomas, the prospect of therapies that can disrupt serotonin’s tumour-promoting role offers a glimmer of hope for more effective treatments and improved outcomes.