Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Abstract
Data availability
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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: EpCAM^lo cells are motile, invasive, chemo-resistant, and highly metastatic. EpCAM^lo 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 EpCAM^lo 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.

The following data sets were generated

(2020) Phenotypic plasticity and partial EMT underlie local invasion and distant metastasis in colon cancer (Bulk RNA-Seq)
NCBI Gene Expression Omnibus, GSE154927.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154927
(2020) Phenotypic plasticity and partial EMT underlie local invasion and distant metastasis in colon cancer (Single cell RNA-Seq)
NCBI Gene Expression Omnibus, GSE154930.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154930

The following previously published data sets were used

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Article and author information

Author details

Andrea Sacchetti

Pathology, Erasmus MC, Rotterdam, Netherlands

Competing interests
The authors declare that no competing interests exist.
Miriam Teeuwssen

Pathology, Erasmus MC, Rotterdam, Netherlands

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Mathijs Verhagen

Pathology, Erasmus MC, Rotterdam, Netherlands

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"This ORCID iD identifies the author of this article:" 0000-0003-3126-8379
Rosalie Joosten

Pathology, Erasmus MC, Rotterdam, Netherlands

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Tong Xu

Pathology, Erasmus MC, Rotterdam, Netherlands

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Roberto Stabile

Pathology, Erasmus MC, Rotterdam, Netherlands

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Berdine van der Steen

Pathology, Erasmus MC, Rotterdam, Netherlands

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Martin M Watson

Pathology, Erasmus MC, Rotterdam, Netherlands

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Alem Gusinac

Pathology, Erasmus MC, Rotterdam, Netherlands

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Won Kyu Kim

Natural Product Research Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea

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Inge Ubink

Department of Surgical Oncology, Cancer Centre, University Medical Centre Utrecht, Utrecht, Netherlands

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Harmen JG Van de Werken

Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands

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"This ORCID iD identifies the author of this article:" 0000-0002-9794-1477
Arianna Fumagalli

n/a, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands

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The authors declare that no competing interests exist.
Madelon Paauwe

n/a, Cancer Research UK Beatson Institute, Glasgow, United Kingdom

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Jacco Van Rheenen

Van Rheenen group, Netherlands Cancer Institute, Amterdam, Netherlands

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Owen J Sansom

Institute of Cancer Sciences, CRUK Beatson Institute, Glasgow, United Kingdom

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9540-3010
Onno Kranenburg

Department of Surgical Oncology, Cancer Centre, University Medical Centre Utrecht, Utrecht, Netherlands

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The authors declare that no competing interests exist.
Riccardo Fodde

Pathology, Erasmus MC, Rotterdam, Netherlands

For correspondence
r.fodde@erasmusmc.nl

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9839-4324

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.

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).

Copyright

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.