Oncotarget

Research Papers:

Wnt signalling is a bi-directional vulnerability of cancer cells

David J. Duffy _, Aleksandar Krstic, Thomas Schwarzl, Melinda Halasz, Kristiina Iljin, Dirk Fey, Bridget Haley, Jenny Whilde, Saija Haapa-Paananen, Vidal Fey, Matthias Fischer, Frank Westermann, Kai-Oliver Henrich, Steffen Bannert, Desmond G. Higgins and Walter Kolch

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Oncotarget. 2016; 7:60310-60331. https://doi.org/10.18632/oncotarget.11203

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Abstract

David J. Duffy1,7,*, Aleksandar Krstic1,*, Thomas Schwarzl1,8, Melinda Halasz1, Kristiina Iljin6, Dirk Fey1, Bridget Haley1, Jenny Whilde1, Saija Haapa-Paananen6, Vidal Fey6, Matthias Fischer5, Frank Westermann4, Kai-Oliver Henrich4, Steffen Bannert4, Desmond G. Higgins1,2,3 , Walter Kolch1,2,3

1Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland

2Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland

3School of Medicine, University College Dublin, Belfield, Dublin, Ireland

4Division of NB Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

5Department of Paediatric Haematology and Oncology and Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany

6VTT Technical Research Centre of Finland, Espoo, Finland

7Current address: The Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, Florida, USA

8Current address: European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

*These authors contributed equally to this work

Correspondence to:

David J. Duffy, email: david.duffy@ucd.ie

Keywords: neuroblastoma, melanoma, colorectal cancer, MYC (c-MYC), mRNA sequencing (mRNA-seq)

Received: November 03, 2015     Accepted: July 26, 2016     Published: August 11, 2016

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.


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