title: Wnt signalling is a bi-directional vulnerability of cancer cells.
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.
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Current address: The Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, Florida, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Duffy
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Krstic
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Current address: European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzl
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Melinda
authors.initials: M
authors.lastname: Halasz
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Fey
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Bridget
authors.initials: B
authors.lastname: Haley
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Jenny
authors.initials: J
authors.lastname: Whilde
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Saija
authors.initials: S
authors.lastname: Haapa-Paananen
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Vidal
authors.initials: V
authors.lastname: Fey
authors.affiliation: Department of Paediatric Haematology and Oncology and Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Division of NB Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.affiliation: Division of NB Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kai-Oliver
authors.initials: KO
authors.lastname: Henrich
authors.affiliation: Division of NB Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Bannert
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland.|School of Medicine, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Higgins
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland.|School of Medicine, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D040901:Proteomics / Q000379:methods; D011744:Pyrimidinones / Q000494:pharmacology; D034622:RNA Interference; D016019:Survival Analysis; D014212:Tretinoin / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D011744:Pyrimidinones; D051153:Wnt Proteins; D051176:beta Catenin; D014212:Tretinoin
keywords: MYC (c-MYC); colorectal cancer; mRNA sequencing (mRNA-seq); melanoma; neuroblastoma