Neuroblastoma Wnt target gene signature identifies prognostic clusters and reveals complex interactions regulating differentiation and proliferation.

Neuroblastoma is one of the commonest and deadliest solid tumours of childhood. It is thought to arise as result of disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. One of the mechanisms by which this occurs is direct transcriptional repression of regulators of differentiation, such as nerve growth factor receptor (NGFR/p75NTR) and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1) by the oncogenic transcription factor MYCN, which is over-expressed in approximately half of poor prognosis neuroblastomas as a result of genomic amplification. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c-MYC has been shown to be activated by Wnt signalling in various tissues. However, our previous work demonstrated that Wnt signalling in neuroblastoma does not induce MYCN and c-MYC. This led us to define the neuroblastoma-specific Wnt-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology. We report the identification of novel Wnt targets likely to be involved in sympathetic nervous system differentiation, and show that Wnt signalling can drive differentiation of neuroblastoma cells. A subset of these differentiation genes are repressed by MYCN. Interrogation of primary tumour databases shows that our Wnt genes can (a) identify prognostic subgroups, and (b) reveal the complex interplay of signalling pathways contributing to the clinical and biological heterogeneity of neuroblastoma.