A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors
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...
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MDPI AG
2023-10-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/10/2719 |
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| author | Janson Tse Ryan O’Keefe Angela Rigopolous Annalisa L. E. Carli Jo Waaler Stefan Krauss Matthias Ernst Michael Buchert |
| author_facet | Janson Tse Ryan O’Keefe Angela Rigopolous Annalisa L. E. Carli Jo Waaler Stefan Krauss Matthias Ernst Michael Buchert |
| author_sort | Janson Tse |
| collection | DOAJ |
| description | 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 <i>APC</i> 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 <i>Apc<sup>flox/flox</sup></i> mice can rescue in utero death of <i>Apc<sup>min/flox</sup></i> mutant conceptus without subsequent post-mortem assessment of WNT/β-catenin signalling. Indeed, the phenotypic plasticity of born <i>Apc<sup>min/flox</sup></i> 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. |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T21:25:22Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-58c1bf05c4fa486e8b60e488ae9330b22023-11-19T15:46:07ZengMDPI AGBiomedicines2227-90592023-10-011110271910.3390/biomedicines11102719A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling InhibitorsJanson Tse0Ryan O’Keefe1Angela Rigopolous2Annalisa L. E. Carli3Jo Waaler4Stefan Krauss5Matthias Ernst6Michael Buchert7Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaCancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaSchool of Cancer Medicine, La Trobe University, Bundoora, VIC 3086, AustraliaCancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaDepartment of Immunology and Transfusion Medicine, Oslo University Hospital, Rikshospitalet, 0424 Oslo, NorwayDepartment of Immunology and Transfusion Medicine, Oslo University Hospital, Rikshospitalet, 0424 Oslo, NorwayCancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaCancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaSpecific 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 <i>APC</i> 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 <i>Apc<sup>flox/flox</sup></i> mice can rescue in utero death of <i>Apc<sup>min/flox</sup></i> mutant conceptus without subsequent post-mortem assessment of WNT/β-catenin signalling. Indeed, the phenotypic plasticity of born <i>Apc<sup>min/flox</sup></i> 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.https://www.mdpi.com/2227-9059/11/10/2719WNT/β-catenin signallingWNT inhibitorsin vivo assaytankyrase inhibitorpyrvinium pamoate<i>APC</i> |
| spellingShingle | Janson Tse Ryan O’Keefe Angela Rigopolous Annalisa L. E. Carli Jo Waaler Stefan Krauss Matthias Ernst Michael Buchert A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors Biomedicines WNT/β-catenin signalling WNT inhibitors in vivo assay tankyrase inhibitor pyrvinium pamoate <i>APC</i> |
| title | A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors |
| title_full | A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors |
| title_fullStr | A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors |
| title_full_unstemmed | A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors |
| title_short | A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors |
| title_sort | mouse model for the rapid and binomial assessment of putative wnt β catenin signalling inhibitors |
| topic | WNT/β-catenin signalling WNT inhibitors in vivo assay tankyrase inhibitor pyrvinium pamoate <i>APC</i> |
| url | https://www.mdpi.com/2227-9059/11/10/2719 |
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