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.
See also:
- All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives);
- Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy;
- Neuroblastoma: Complete objective response to biological treatment.
Wnt signalling is a bi-directional vulnerability of cancer cells - Supplementary Information
Wnt signalling is a bi-directional vulnerability of cancer cells - Supplementary Table 1
Wnt signalling is a bi-directional vulnerability of cancer cells - Supplementary Table 2
Wnt signalling is a bi-directional vulnerability of cancer cells - Supplementary Table 3