Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
- Erasmus MC, Netherlands
- Korea Institute of Science and Technology, Republic of Korea
- University Medical Centre Utrecht, Netherlands
- Princess Máxima Center for Pediatric Oncology, Netherlands
- Cancer Research UK Beatson Institute, United Kingdom
- Netherlands Cancer Institute, Netherlands
- CRUK Beatson Institute, United Kingdom
Abstract
Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphologic and functional features while en route to the metastatic site. However, the study of phenotypic plasticity is hindered by the rarity of these events within primary lesions and by the lack of experimental models. Here, we identified a subpopulation of phenotypic plastic colon cancer cells: EpCAMlo cells are motile, invasive, chemo-resistant, and highly metastatic. EpCAMlo bulk and single-cell RNAseq analysis indicated 1. enhanced Wnt/b-catenin signaling, 2. a broad spectrum of degrees of EMT activation including hybrid E/M states (partial EMT) with highly plastic features, and 3. high correlation with the CMS4 subtype, accounting for colon cancer cases with poor prognosis and a pronounced stromal component. Of note, a signature of genes specifically expressed in EpCAMlo cancer cells is highly predictive of overall survival in tumors other than CMS4, thus highlighting the relevance of quasi-mesenchymal tumor cells across the spectrum of colon cancers. Enhanced Wnt and the downstream EMT activation represent key events in eliciting phenotypic plasticity along the invasive front of primary colon carcinomas. Distinct sets of epithelial and mesenchymal genes define transcriptional trajectories through which state transitions arise. pEMT cells, often earmarked by the extracellular matrix glycoprotein SPARC together with nuclear ZEB1 and b-catenin along the invasive front of primary colon carcinomas, are predicted to represent the origin of these (de)differentiation routes through biologically-distinct cellular states, and to underlie the phenotypic plasticity of colon cancer cells.
Data availability
The RNA-sequencing data from this study have been submitted to the Gene Expression Omnibus (GEO) database under the accession number GSE154927 and GSE154930 for the bulk and single-cell RNAseq data, respectively.
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Single cell 3' RNA sequencing of 6 Belgian colorectal cancer patientsNCBI Gene Expression Omnibus, GSE144735.
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Single cell 3' RNA sequencing of 23 Korean colorectal cancer patientsNCBI Gene Expression Omnibus, GSE132465.
Article and author information
Author details
Harmen JG Van de Werken
Funding
Maag Lever Darm Stichting (FP 15-09)
- Riccardo Fodde
KWF Kankerbestrijding (EMCR 2015-8090)
- Riccardo Fodde
Cancer Research UK (A17196/A21139)
- Owen J Sansom
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Margaret C Frame, University of Edinburgh, United Kingdom
Ethics
Animal experimentation: All protocols involving animals were approved by the Dutch Animal Experimental Committee and were conformed to the Code of Practice for Animal Experiments in Cancer Research established by the Netherlands Inspectorate for Health Protections, Commodities and Veterinary Public health (The Hague, the Netherlands, 1999).
Version history
- Received: July 26, 2020
- Accepted: May 17, 2021
- Accepted Manuscript published: May 26, 2021 (version 1)
- Version of Record published: June 10, 2021 (version 2)
Copyright
© 2021, Sacchetti et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
eLife 10:e61461.
https://doi.org/10.7554/eLife.61461
