Journal Article

3D imaging of colorectal cancer organoids identifies responses to Tankyrase inhibitors

Buchstaller, Hans-Peter, Ewan, Kenneth B., Boj, Sylvia, Esdar, Christina, Herpers, Bram, Dale, Trevor C., Hollins, Andrew J., Ramezanpour, Bahar, Shaw, Paul H., Naven, Marc, Price, Leo S., Badder, Delyth A., Ashelford, Kevin E., Badder, Luned M., Treherne, J. Mark, Yan, Kuan, Thomas, Mairian, Shone, Jennifer R., Hargest, Rachel, Clarke, Alan R., Wienke, Dirk

2020

Overview

Aberrant activation of the Wnt signalling pathway is required for tumour initiation and survival in the majority of colorectal cancers. The development of inhibitors of Wnt signalling has been the focus of multiple drug discovery programs targeting colorectal cancer and other malignancies associated with aberrant pathway activation. However, progression of new clinical entities targeting the Wnt pathway has been slow. One challenge lies with the limited predictive power of 2D cancer cell lines because they fail to fully recapitulate intratumoural phenotypic heterogeneity. In particular, the relationship between 2D cancer cell biology and cancer stem cell function is poorly understood. By contrast, 3D tumour organoids provide a platform in which complex cell-cell interactions can be studied. However, complex 3D models provide a challenging platform for the quantitative analysis of drug responses of therapies that have differential effects on tumour cell subpopulations. Here, we generated tumour organoids from colorectal cancer patients and tested their responses to inhibitors of Tankyrase (TNKSi) which are known to modulate Wnt signalling. Using compounds with 3 orders of magnitude difference in cellular mechanistic potency together with image-based assays, we demonstrate that morphometric analyses can capture subtle alterations in organoid responses to Wnt inhibitors that are consistent with activity against a cancer stem cell subpopulation. Overall our study highlights the value of phenotypic readouts as a quantitative method to asses drug-induced effects in a relevant preclinical model.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Biology and Life Sciences / Cancer / Cell culture / Cell interactions / Colorectal cancer / Colorectal carcinoma / Development and progression / Diagnosis / Drug therapy / Enzyme inhibitors / Funding / Gastrointestinal cancer / Genetics / Heterogeneity / Inhibitors / Kinases / Medical research / Medicine and Health Sciences / Metabolism / Organoids / Quantitative analysis / R&D / Research & development / Research and Analysis Methods / Signal transduction / Signaling / Software / Stem cells / Subpopulations / Supervision / Testing / Three dimensional models / Three-dimensional imaging / Tissue culture / Tumor cell lines / Tumors / Wnt protein