Wnt signalling is a bi-directional vulnerability of cancer cells

David J. Duffy (Corresponding Author), Aleksandar Krstic (Corresponding Author), 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

    Research output: Contribution to journalArticleScientificpeer-review

    16 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)60310-60331
    JournalOncotarget
    Volume7
    Issue number37
    DOIs
    Publication statusPublished - 2016
    MoE publication typeA1 Journal article-refereed

    Keywords

    • neuroblastoma
    • melanoma
    • colorectal cancer
    • MYC (c-MYC)
    • mRNA sequencing (mRNA-seq)

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