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

13 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

Fingerprint

Catenins
Neuroblastoma
Neoplasms
Therapeutics
Tretinoin
Colorectal Neoplasms
Melanoma
Cell Proliferation
Apoptosis
Neoplasm Metastasis
Recurrence
DNA
Genes

Keywords

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

Cite this

Duffy, D. J., Krstic, A., Schwarzl, T., Halasz, M., Iljin, K., Fey, D., ... 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
Duffy, David J. ; Krstic, Aleksandar ; Schwarzl, Thomas ; Halasz, Melinda ; Iljin, Kristiina ; Fey, Dirk ; Haley, Bridget ; Whilde, Jenny ; Haapa-Paananen, Saija ; Fey, Vidal ; Fischer, Matthias ; Westermann, Frank ; Henrich, Kai-Oliver ; Bannert, Steffen ; Higgins, Desmond G. ; Kolch, Walter. / Wnt signalling is a bi-directional vulnerability of cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 37. pp. 60310-60331.
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Duffy, DJ, 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, DG & Kolch, W 2016, 'Wnt signalling is a bi-directional vulnerability of cancer cells', Oncotarget, vol. 7, no. 37, pp. 60310-60331. https://doi.org/10.18632/oncotarget.11203

Wnt signalling is a bi-directional vulnerability of cancer cells. / Duffy, David J. (Corresponding Author); Krstic, Aleksandar (Corresponding Author); Schwarzl, Thomas; Halasz, Melinda; Iljin, Kristiina; Fey, Dirk; Haley, Bridget; Whilde, Jenny; Haapa-Paananen, Saija; Fey, Vidal; Fischer, Matthias; Westermann, Frank; Henrich, Kai-Oliver; Bannert, Steffen; Higgins, Desmond G.; Kolch, Walter.

In: Oncotarget, Vol. 7, No. 37, 2016, p. 60310-60331.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Wnt signalling is a bi-directional vulnerability of cancer cells

AU - Duffy, David J.

AU - Krstic, Aleksandar

AU - Schwarzl, Thomas

AU - Halasz, Melinda

AU - Iljin, Kristiina

AU - Fey, Dirk

AU - Haley, Bridget

AU - Whilde, Jenny

AU - Haapa-Paananen, Saija

AU - Fey, Vidal

AU - Fischer, Matthias

AU - Westermann, Frank

AU - Henrich, Kai-Oliver

AU - Bannert, Steffen

AU - Higgins, Desmond G.

AU - Kolch, Walter

N1 - Project code: 100167

PY - 2016

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N2 - 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.

AB - 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.

KW - neuroblastoma

KW - melanoma

KW - colorectal cancer

KW - MYC (c-MYC)

KW - mRNA sequencing (mRNA-seq)

U2 - 10.18632/oncotarget.11203

DO - 10.18632/oncotarget.11203

M3 - Article

VL - 7

SP - 60310

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JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

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Duffy DJ, Krstic A, Schwarzl T, Halasz M, Iljin K, Fey D et al. Wnt signalling is a bi-directional vulnerability of cancer cells. Oncotarget. 2016;7(37):60310-60331. https://doi.org/10.18632/oncotarget.11203