Universität zu Köln

Duffy, David J., Krstic, Aleksandar, Schwarzl, Thomas ORCID: 0000-0001-7697-7000, Halasz, Melinda ORCID: 0000-0002-6175-9630, Iljin, Kristiina, Fey, Dirk ORCID: 0000-0002-5558-0167, Haley, Bridget, Whilde, Jenny, Haapa-Paananen, Saija, Fey, Vidal, Fischer, Matthias, Westermann, Frank, Henrich, Kai-Oliver, Bannert, Steffen, Higgins, Desmond G. and Kolch, Walter (2016). Wnt signalling is a bi-directional vulnerability of cancer cells. Oncotarget, 7 (37). S. 60310 - 60332. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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/beta-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 beta-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 beta-catenin signalling, which repress normal beta-catenin mediated transcriptional regulation. A beta-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This beta-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/beta-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Duffy, David J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krstic, Aleksandar UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarzl, Thomas UNSPECIFIED orcid.org/0000-0001-7697-7000 UNSPECIFIED Halasz, Melinda UNSPECIFIED orcid.org/0000-0002-6175-9630 UNSPECIFIED Iljin, Kristiina UNSPECIFIED UNSPECIFIED UNSPECIFIED Fey, Dirk UNSPECIFIED orcid.org/0000-0002-5558-0167 UNSPECIFIED Haley, Bridget UNSPECIFIED UNSPECIFIED UNSPECIFIED Whilde, Jenny UNSPECIFIED UNSPECIFIED UNSPECIFIED Haapa-Paananen, Saija UNSPECIFIED UNSPECIFIED UNSPECIFIED Fey, Vidal UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Westermann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Henrich, Kai-Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Bannert, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Higgins, Desmond G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolch, Walter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-262395
DOI:	10.18632/oncotarget.11203
Journal or Publication Title:	Oncotarget
Volume:	7
Number:	37
Page Range:	S. 60310 - 60332
Date:	2016
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GLYCOGEN-SYNTHASE KINASE-3; SMALL-MOLECULE INHIBITORS; BETA-CATENIN EXPRESSION; COLORECTAL-CANCER; STEM-CELLS; RETINOIC ACID; NEUROBLASTOMA; PATHWAY; MELANOMA; GROWTH Multiple languages Oncology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26239