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

Szemes, Marianna; Melegh, Zsombor; Bellamy, Jacob; Greenhough, Alexander; Kollareddy, Madhu; Catchpoole, Daniel; Malik, Karim

Abstract

The Wnt and bone morphogenetic protein (BMP) signaling 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 tumor arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/β-catenin signaling 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 characterised the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signaling and BMP4-induced growth suppression and differentiation. An immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumors, in contrast to a high expression in ganglion cells. These results are consistent with a tumor suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signaling, verified by increases of Notch3 and Hes1 proteins. Together, our data demonstrate, for the first time, Wnt-BMP-Notch signaling crosstalk associated with growth suppression of neuroblastoma.

• Journal Article Type: Article
• Acceptance Date: Mar 19, 2020
• Online Publication Date: Mar 23, 2020
• Publication Date: Mar 23, 2020
• Deposit Date: Jan 20, 2021
• Publicly Available Date: Jan 20, 2021
• Journal: Cells
• Electronic ISSN: 2073-4409
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 3
• Article Number: 783
• DOI: https://doi.org/10.3390/cells9030783
• Keywords: neuroblastoma; BMP4; Wnt and Notch signaling; RNA sequencing; growth inhibition
• Public URL: https://uwe-repository.worktribe.com/output/7003054
• Publisher URL: https://www.mdpi.com/2073-4409/9/3/783