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3D imaging of colorectal cancer organoids identifies responses to Tankyrase inhibitors
- Source :
- PLoS ONE, Vol 15, Iss 8, p e0235319 (2020), PLoS ONE
- Publication Year :
- 2020
- Publisher :
- Public Library of Science, 2020.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Colorectal cancer
medicine.medical_treatment
Mice, SCID
Mice
0302 clinical medicine
Cell Signaling
Mice, Inbred NOD
Gastrointestinal Cancers
Medicine and Health Sciences
Organ Cultures
Enzyme Inhibitors
WNT Signaling Cascade
Tankyrases
Multidisciplinary
Drug discovery
Stem Cell Therapy
Wnt signaling pathway
Stem-cell therapy
Phenotype
Signaling Cascades
Organoids
Oncology
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Medicine
Female
Biological Cultures
Colorectal Neoplasms
Research Article
Signal Transduction
Adult
Signal Inhibition
Imaging Techniques
Science
Antineoplastic Agents
Gastroenterology and Hepatology
Biology
Research and Analysis Methods
03 medical and health sciences
Imaging, Three-Dimensional
Cancer stem cell
medicine
Organoid
Animals
Humans
Colorectal Cancer
Clinical Genetics
Morphometry
Cancers and Neoplasms
Biology and Life Sciences
Cell Biology
medicine.disease
030104 developmental biology
Cancer cell
Cancer research
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Database :
- OpenAIRE
- Journal :
- PLoS ONE, Vol 15, Iss 8, p e0235319 (2020), PLoS ONE
- Accession number :
- edsair.doi.dedup.....eaf18a324f5b253e614df4ccc90f0b7b