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Wnt signalling is a bi-directional vulnerability of cancer cells
David J Duffy1,2, Aleksandar Krstic1, Thomas Schwarzl1,3
1Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
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.
Insights
Wnt/β-catenin signaling is a dual-action vulnerability in cancers like neuroblastoma. Both activating and inhibiting this pathway show therapeutic promise, offering new strategies for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Wnt signaling plays a critical role in cancer development, metastasis, and relapse.
- The therapeutic potential of targeting Wnt signaling in cancer remains debated, with conflicting evidence regarding pathway activation versus inhibition.
- Neuroblastoma, malignant melanoma, and colorectal cancer are among the diverse malignancies influenced by Wnt signaling.
Purpose of the Study:
- To investigate the therapeutic potential of modulating Wnt/β-catenin signaling in various cancer types.
- To explore the effects of both Wnt pathway hyper-activation and inhibition on cancer cells.
- To identify predictive biomarkers for Wnt-directed cancer therapies.
Main Methods:
- Analysis of Wnt/β-catenin signaling in neuroblastoma, malignant melanoma, and colorectal cancer models.
- Assessment of cancer cell apoptosis, proliferation, and differentiation following pathway modulation.
- Investigation of cross-talk between MYCN and β-catenin signaling.
- Development and validation of a β-catenin target gene signature for patient outcome prediction.
Main Results:
- Wnt/β-catenin signaling acts as a bi-directional vulnerability in neuroblastoma, malignant melanoma, and colorectal cancer.
- Hyper-activation of Wnt signaling induces apoptosis in cancer cells, including those with oncogenic β-catenin.
- Wnt inhibition suppresses cancer cell proliferation and promotes neuroblastoma differentiation.
- Novel cross-talk between MYCN and β-catenin signaling was identified, impacting transcriptional regulation.
- A β-catenin target gene signature and TCF/LEF expression levels predict patient outcomes.
Conclusions:
- Wnt/β-catenin signaling represents a versatile therapeutic target in multiple cancer types, with both activation and inhibition offering potential benefits.
- The bi-directional nature of Wnt signaling vulnerability suggests adaptable treatment strategies.
- A β-catenin signature can identify neuroblastoma patients who may benefit from Wnt-targeted therapies.
- Wnt signaling's role as a conserved feature of malignant cells warrants further investigation.
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