Wnt signalling is a bi-directional vulnerability of cancer cells

• DOI: 10.18632/oncotarget.11203
• Publication Date: 2016-08-11T18:56:55Z
• Authors: 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; Walter Kolch
• Keywords: Proteomics; 0301 basic medicine; 570; colorectal cancer; Antineoplastic Agents; Tretinoin; Pyrimidinones; MYC (c-MYC); neuroblastoma; Neuroblastoma; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Cell Line, Tumor; melanoma; Humans; Melanoma; Wnt Signaling Pathway; beta Catenin; Cell Proliferation; N-Myc Proto-Oncogene Protein; Gene Expression Profiling; mRNA sequencing (mRNA-seq); ta1182; Cell Differentiation; ta3122; Bridged Bicyclo Compounds, Heterocyclic; Colorectal cancer; Survival Analysis; 3. Good health; Gene Expression Regulation, Neoplastic; Wnt Proteins; RNA Interference; Research Paper

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.