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Wnt Signalling Drives Context-Dependent Differentiation or Proliferation in Neuroblastoma

Szemes, Marianna; Melegh, Zsombor B; Greenhough, Alexander; Malik, Sally; Yuksel, Aysen; Catchpoole, Daniel; Kollareddy, Madhu R; Gallacher, Kelli; Park, Ji Hyun; Malik, Karim


Marianna Szemes

Zsombor B Melegh

Sally Malik

Aysen Yuksel

Daniel Catchpoole

Madhu R Kollareddy

Kelli Gallacher

Ji Hyun Park

Karim Malik


© 2018 Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra- and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. 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 Wnt3a/Rspo2 treatment of some neuroblastoma cell lines can, paradoxically, decrease c-MYC and MYCN proteins. This prompted us to define the neuroblastoma-specific Wnt3a/Rspo2-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology. Here we report the identification of ninety Wnt target genes, and show that Wnt signalling is upstream of numerous transcription factors and signalling pathways in neuroblastoma. Using live-cell imaging, we show that Wnt signalling can drive differentiation of SK-N-BE(2)-C and SH-SY5Y cell-lines, but, conversely, proliferation of SK-N-AS cells. We show that cell-lines that differentiate show induction of pro-differentiation BMP4 and EPAS1 proteins, which is not apparent in the SK-N-AS cells. In contrast, SK-N-AS cells show increased CCND1, phosphorylated RB and E2F1 in response to Wnt3a/Rspo2, consistent with their proliferative response, and these proteins are not increased in differentiating lines. By meta-analysis of the expression of our 90 genes in primary tumour gene expression databases, we demonstrate discrete expression patterns of our Wnt genes in patient cohorts with different prognosis. Furthermore our analysis reveals interconnectivity within subsets of our Wnt genes, with one subset comprised of novel putative drivers of neuronal differentiation repressed by MYCN. Assessment of β-catenin immunohistochemistry shows high levels of β-catenin in tumours with better differentiation, further supporting a role for canonical Wnt signalling in neuroblastoma differentiation.


Szemes, M., Greenhough, A., Melegh, Z. B., Malik, S., Yuksel, A., Catchpoole, D., …Malik, K. (2018). Wnt Signalling Drives Context-Dependent Differentiation or Proliferation in Neuroblastoma. Neoplasia, 20(4), 335-350.

Journal Article Type Article
Acceptance Date Jan 21, 2018
Online Publication Date Mar 3, 2018
Publication Date Apr 1, 2018
Journal Neoplasia (United States)
Print ISSN 1522-8002
Electronic ISSN 1476-5586
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 20
Issue 4
Pages 335-350
Public URL
Publisher URL


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