Journal
ONCOTARGET
Volume 7, Issue 37, Pages 60310-60331Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11203
Keywords
neuroblastoma; melanoma; colorectal cancer; MYC (c-MYC); mRNA sequencing (mRNA-seq)
Categories
Funding
- European Union [FP7-HEALTH-2010-259348-2]
- Science Foundation Ireland (SFI) [06/CE/B1129]
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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/beta-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 beta-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 beta-catenin signalling, which repress normal beta-catenin mediated transcriptional regulation. A beta-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This beta-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/beta-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.
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