Wnt signalling is a bi-directional vulnerability of cancer cells

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Title: Wnt signalling is a bi-directional vulnerability of cancer cells
Authors: Duffy, David J.
Krstic, Aleksandar
Schwarzl, Thomas
Halasz, Melinda
Fey, Dirk
Haley, Bridget
Whilde, Jenny
Higgins, Desmond G
Kolch, Walter
Permanent link: http://hdl.handle.net/10197/9772
Date: 11-Aug-2016
Online since: 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.
Funding Details: 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
Keywords: MYC (c-MYC)Colorectal cancermRNA sequencing (mRNA-seq)MelanomaNeuroblastoma
DOI: 10.18632/oncotarget.11203
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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