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Wnt signalling is a bi-directional vulnerability of cancer cells
Date Issued
2016-08-11
Date Available
2019-04-02T11:44:55Z
Abstract
Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by β-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and β-catenin signalling, which repress normal β-catenin mediated transcriptional regulation. A β-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This β-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/β-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.
Sponsorship
European Commission - Seventh Framework Programme (FP7)
Science Foundation Ireland
Type of Material
Journal Article
Publisher
Impact Journals
Journal
Oncotarget
Volume
7
Issue
37
Start Page
60310
End Page
60331
Copyright (Published Version)
2016 the Authors
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
File(s)
Name
Oncotarget Wnt signalling is a bi-directional vulnerability of cancer cells.pdf
Size
9.12 MB
Format
Owning collection
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