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.
Higgins, Desmond G
|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 cancer; mRNA sequencing (mRNA-seq); Melanoma; Neuroblastoma||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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