Specific projects include:
1. The biochemistry of Wnt pathway components such as the kinase GSK-3
2. The identification of novel Wnt regulators through high throughput cDNA, siRNA and drug screening.
3. The analysis of normal and oncogenic Wnt signalling using murine models and 3D organoid culture systems.
4. The loss of the Axin anti-oncogenes in liver cancer.
Title: The practical challenges of using organoids in drug discovery.
Author: Luned M. Badder1, Andrew J. Hollins1, Kenneth Ewan1, Bram Herpers1, Kuan Yan1, Jennifer Shone1, Delyth A.Badder1, Rachel Hargest1, Alan R.Clarke, Dirk Wienke1, Leo S.Price2, Paul Shaw2, Trevor C.Dale2*
1. Cardiff University, Wales, UK, 2. OcellO, Leiden, Netherlands.
Organoid models have huge potential within drug discovery as they appear to be better predictors of efficacy. Using organoids derived from genetically modified mice we show that responses to inhibitors of the Wnt pathway recapitulate cancer-relevant biology better than culture-adapted cancer cell lines. We also show that the complex biology exhibited by human colorectal cancer organoids are best analysed by multiparametric imaging assays that are compatible with high throughput analysis. Our findings demonstrate that 3D culture models combined with imaging readouts may be most applicable in contexts when stem cell biology is contributes to drug response phenotypes.
1. Jardé, T. et al. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids. Nature Communications 7, 13207 (2016).
2. Clarke, P. A. et al. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. eLife 5, (2016).
3. Dale, T. et al. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nature Chemical Biology 11, 973–980 (2015)