Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways

Greenhough

Malik

2018

Preprint

The neural crest, which has been referred to as the fourth germ layer, comprises a multipotent cell population which will specify diverse cells and tissues, including craniofacial cartilage and bones, melanocytes, the adrenal medulla and the peripheral nervous system. These cell fates are known to be determined by gene regulatory networks (GRNs) acting at various stages of neural crest development, such as induction, specification, and migration. Although transcription factor hierarchies and some of their interplay with morphogenetic signalling pathways have been characterised, the full complexity of activities required for regulated development remains uncharted. Deregulation of these pathways may contribute to tumourigenesis, as in the case of neuroblastoma, a frequently lethal embryonic cancer thought to arise from the sympathoadrenal lineage of the neural crest.In this conceptual analysis, we utilise next generation sequencing data from neuroblastoma cells and tumours to evaluate the possible influences of Wnt signalling on neural crest GRNs and on neuroblastoma cell lineages. We provide evidence that Wnt signalling is a major determinant of regulatory networks that underlie mesenchymal/NCClike cell identities through PRRX1 and YAP/TAZ transcription factors. Furthermore, Wnt may also co-operate with Hedgehog signalling in driving proneural differentiation programmes along the adrenergic lineage. We propose that elucidation of Signalling Regulatory Networks can augment and complement GRNs in characterising cell identities, which will in turn contribute to the design of improved therapeutics tailored to primary and relapsing neuroblastoma.

Section: Neuroblastoma and Wnt Signallingcontrasting

confidence: 96%

Wnt signalling is a major determinant of neuroblastoma cell lineages

Greenhough

Malik

2018

Preprint

“…Examples include high FZD1 expression associated with chemoresistance [21], FZD6 marking highly tumorigenic stem-like cells in mouse and human neuroblastoma [22], and FZD2-dependent proliferation of neuroblastoma lines [23].…”

Section: Introductionmentioning

confidence: 99%

Wnt signalling drives context-dependent differentiation or proliferation in neuroblastoma

Greenhough

Melegh

et al. 2018

Preprint

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

“…In particular, the role of the Wnt signalling pathway, often clearly oncogenic in both adult and childhood cancers such as colorectal cancer and Wilms' tumour (1), has been found to exert more complex influences in NB, as shown several laboratories, including ours. These data have indicated Wnt-induced growth promotion or suppression (13,16,40,41), modulation of signalling and transcriptional pathways, interactions with MYCN (16,41), and underlying changes in differentiation states contributing to neuroblastoma tumour heterogeneity (16,19). In this study, we define a Wnt-BMP growth inhibitory axis in neuroblastoma, identifying MSX and Notch signalling as downstream mediators of growth suppression.…”

Section: Discussionmentioning

confidence: 87%

A Wnt-BMP4 signalling axis induces MSX and NOTCH proteins and promotes growth suppression and differentiation in neuroblastoma

Melegh

Bellamy

et al. 2020

Preprint

The Wnt and bone morphogenetic protein (BMP) signalling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumour arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/β-catenin signalling can have cell-type specific effects on neuroblastoma phenotypes, including growth inhibition and differentiation, and that BMP4 mRNA and protein were induced by Wnt3a/Rspo2. In this study, we characterise the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signalling and BMP4-induced growth suppression and differentiation. Immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumours, in contrast to high expression in ganglion cells. These results are consistent with a tumour suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signalling, verified by increases of Notch3 and Hes1 proteins. Together, our data demonstrate for the first time Wnt-BMP-Notch signalling crosstalk associated with growth suppression of neuroblastoma.