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Title: A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors.
Austin Authors: Tse, Janson;O'Keefe, Ryan;Rigopolous, Angela;Carli, Annalisa L E;Waaler, Jo;Krauss, Stefan;Ernst, Matthias ;Buchert, Michael 
Affiliation: Olivia Newton-John Cancer Research Institute
School of Cancer Medicine, La Trobe University, Bundoora, VIC 3086, Australia.
Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway.
Department of Immunology and Transfusion Medicine, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway.;Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway.
Issue Date: 7-Oct-2023
Date: 2023
Publication information: Biomedicines 2023-10-07; 11(10)
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 Apcflox/flox mice can rescue in utero death of Apcmin/flox mutant conceptus without subsequent post-mortem assessment of WNT/β-catenin signalling. Indeed, the phenotypic plasticity of born Apcmin/flox 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.
DOI: 10.3390/biomedicines11102719
ORCID: 0000-0002-8527-2165
Journal: Biomedicines
PubMed URL: 37893093
Type: Journal Article
Subjects: APC
WNT inhibitors
WNT/β-catenin signalling
in vivo assay
pyrvinium pamoate
tankyrase inhibitor
Appears in Collections:Journal articles

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