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A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors
Janson Tse1, Ryan O'Keefe1,2, Angela Rigopolous2,3
1Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
Abstract:
Specific signalling thresholds of the WNT/β-catenin pathway affect embryogenesis and tissue homeostasis in the adult, with mutations in this pathway frequently occurring in cancer. Excessive WNT/β-catenin activity inhibits murine anterior development associated with embryonic lethality and accounts for the driver event in 80% of human colorectal cancers. Uncontrolled WNT/β-catenin signalling arises primarily from impairment mutation in the tumour suppressor gene APC that otherwise prevents prolonged stabilisation of β-catenin. Surprisingly, no inhibitor compounds for WNT/β-catenin signalling have reached clinical use in part owing to the lack of specific in vivo assays that discriminate between on-target activities and dose-limiting toxicities. Here, we present a simple in vivo assay with a binary outcome whereby the administration of candidate compounds to pregnant and phenotypically normal Apc mice can rescue in utero death of Apc mutant conceptus without subsequent post-mortem assessment of WNT/β-catenin signalling. Indeed, the phenotypic plasticity of born Apc conceptus enables future refinement of our assay to potentially enable dosage finding and cross-compound comparisons. Thus, we show for the first time the suitability of endogenous WNT/β-catenin signalling during embryonic development to provide an unambiguous and sensitive mammalian in vivo model to assess the efficacy and bioavailability of potential WNT/β-catenin antagonists.
Insights
A novel WNT/β-catenin inhibitor assay uses mouse embryos to assess drug efficacy. This method rescues embryonic lethality in Apc mutant mice, offering a sensitive in vivo model for drug development.
Area of Science:
- Developmental Biology
- Cancer Biology
- Pharmacology
Background:
- The WNT/β-catenin pathway is crucial for embryogenesis and tissue homeostasis.
- Mutations in this pathway, particularly in the APC gene, drive numerous cancers, including colorectal cancer.
- Lack of specific in vivo assays hinders the clinical development of WNT/β-catenin inhibitors.
Purpose of the Study:
- To develop a simple, sensitive in vivo assay for evaluating WNT/β-catenin inhibitor compounds.
- To utilize embryonic development as a readout for WNT/β-catenin pathway modulation.
- To overcome limitations of current assays in discriminating on-target effects from toxicities.
Main Methods:
- Administration of candidate compounds to pregnant, phenotypically normal Apc mice.
- Assessment of rescue of in utero death in Apc mutant conceptuses as a binary outcome.
- Utilizing the phenotypic plasticity of born Apc conceptus for assay refinement.
Main Results:
- Demonstrated a simple in vivo assay with a binary outcome for WNT/β-catenin antagonists.
- Successfully rescued in utero death of Apc mutant conceptuses.
- Established an unambiguous and sensitive mammalian in vivo model for drug assessment.
Conclusions:
- The developed assay is suitable for assessing the efficacy and bioavailability of WNT/β-catenin antagonists.
- Endogenous WNT/β-catenin signalling during embryonic development provides a robust model system.
- This assay facilitates future dosage finding and cross-compound comparisons for WNT pathway inhibitors.
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