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

14 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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    Duffy, D. J., Krstic, A., Schwarzl, T., Halasz, M., Iljin, K., Fey, D., Haley, B., Whilde, J., Haapa-Paananen, S., Fey, V., Fischer, M., Westermann, F., Henrich, K-O., Bannert, S., Higgins, D. G., & Kolch, W. (2016). Wnt signalling is a bi-directional vulnerability of cancer cells. Oncotarget, 7(37), 60310-60331. https://doi.org/10.18632/oncotarget.11203