Neuroblastoma (NB), accounting for 6–10% of all childhood cancers, is the most common cause of cancer-related deaths in children under five. Despite advances in cancer research, treatment remains challenging due to limited targeted therapies and imprecise risk stratification. NB originates from neural crest (NC)-derived progenitors and is characterised by a failure in neuroblast differentiation. Notably, NB rarely features recurrent point mutations but displays extensive transcriptional and epigenetic dysregulation, suggesting that alterations in gene expression, rather than genetic mutations, are key drivers of tumorigenesis.
This project aims to elucidate the transcriptional regulatory networks governing sympathetic neuron differentiation and how their disruption contributes to NB development. By identifying key transcription factors (TFs) that mediate the transition from proliferative neuroblasts to mature sympathetic neurons, we seek to uncover critical regulators that may act as biomarkers or therapeutic targets.
We used our in vitro sympathetic neurogenesis model, derived from human induced pluripotent stem cells (hiPSCs), to generate bulk and single-cell RNA sequencing data and identify TFs dynamically regulated during neuroblast differentiation. Based on this dataset, we selected candidate TFs potentially involved in NB pathogenesis. We also assess the relationship between TF expression and patient survival, identifying those whose high or low expression correlates with prognosis. Next, we will determine whether these TFs are dysregulated in NB and assess the impact of their manipulation on differentiation. Functional studies using gain- and loss-of-function approaches will clarify their roles in differentiation blockade and tumour progression.
Ultimately, this research will contribute to a deeper understanding of NB pathogenesis and support the development of precision medicine strategies for this aggressive paediatric cancer.