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

Autor: Badder LM; Cardiff University School of Biosciences, Cardiff, Wales, United Kingdom.; European Cancer Stem Cell Research Institute (ECSCRI), Cardiff University, Cardiff, Wales, United Kingdom., Hollins AJ; Cardiff University School of Biosciences, Cardiff, Wales, United Kingdom.; European Cancer Stem Cell Research Institute (ECSCRI), Cardiff University, Cardiff, Wales, United Kingdom., Herpers B; OcellO B.V., Leiden, The Netherlands., Yan K; OcellO B.V., Leiden, The Netherlands., Ewan KB; Cardiff University School of Biosciences, Cardiff, Wales, United Kingdom., Thomas M; Cellesce Ltd, Cardiff Medicentre, Heath Park, Cardiff, United Kingdom., Shone JR; Cardiff University School of Biosciences, Cardiff, Wales, United Kingdom., Badder DA; Cellular Pathology Department, University Hospital for Wales, Cardiff, United Kingdom., Naven M; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom., Ashelford KE; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom., Hargest R; Department of Colorectal Surgery, University Hospital of Wales, Cardiff, United Kingdom.; Division of Cancer and Genetics, CCMRC, Henry Wellcome Building, Cardiff University, Cardiff, United Kingdom., Clarke AR; European Cancer Stem Cell Research Institute (ECSCRI), Cardiff University, Cardiff, Wales, United Kingdom., Esdar C; Biopharma, Merck Healthcare KGaA, Research & Development, Darmstadt, Germany., Buchstaller HP; Biopharma, Merck Healthcare KGaA, Research & Development, Darmstadt, Germany., Treherne JM; Cellesce Ltd, Cardiff Medicentre, Heath Park, Cardiff, United Kingdom., Boj S; Hubrecht Organoid Technology, Utrecht, The Netherlands., Ramezanpour B; Hubrecht Organoid Technology, Utrecht, The Netherlands., Wienke D; Biopharma, Merck Healthcare KGaA, Research & Development, Darmstadt, Germany., Price LS; OcellO B.V., Leiden, The Netherlands., Shaw PH; Velindre Cancer Centre, Cardiff, Wales, United Kingdom., Dale TC; European Cancer Stem Cell Research Institute (ECSCRI), Cardiff University, Cardiff, Wales, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Aug 18; Vol. 15 (8), pp. e0235319. Date of Electronic Publication: 2020 Aug 18 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0235319
Abstrakt: 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.
Competing Interests: L.S.P is a founder and major shareholder of OcellO B.V, and C.E., H.-P.B and D.W are employees of Merck Healthcare KGaA. M.T and J.T are employees of Cellesce Ltd.T.C.D is a director of Cellesce Ltd. L.M.B and D.A.B are siblings. The funder provided support in the form of salaries for authors L.S.P, C.E.,H.-P.B, D.W, M.T and J.T but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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