Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphological and functional features while en route to the metastatic site. However, the study of phenotypic plasticity is hindered by the rarity of these...

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Autores principales:	Andrea Sacchetti, Miriam Teeuwssen, Mathijs Verhagen, Rosalie Joosten, Tong Xu, Roberto Stabile, Berdine van der Steen, Martin M Watson, Alem Gusinac, Won Kyu Kim, Inge Ubink, Harmen JG Van de Werken, Arianna Fumagalli, Madelon Paauwe, Jacco Van Rheenen, Owen J Sansom, Onno Kranenburg, Riccardo Fodde
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	partial EMT colon cancer phenotypic plasticity Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/edd28e2414b842c4998587deaa94f069
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spelling	oai:doaj.org-article:edd28e2414b842c4998587deaa94f0692021-11-23T13:03:09ZPhenotypic plasticity underlies local invasion and distant metastasis in colon cancer10.7554/eLife.614612050-084Xe61461https://doaj.org/article/edd28e2414b842c4998587deaa94f0692021-05-01T00:00:00Zhttps://elifesciences.org/articles/61461https://doaj.org/toc/2050-084XPhenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphological 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/β-catenin signaling, (2) a broad spectrum of degrees of epithelial to mesenchymal transition (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 β-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.Andrea SacchettiMiriam TeeuwssenMathijs VerhagenRosalie JoostenTong XuRoberto StabileBerdine van der SteenMartin M WatsonAlem GusinacWon Kyu KimInge UbinkHarmen JG Van de WerkenArianna FumagalliMadelon PaauweJacco Van RheenenOwen J SansomOnno KranenburgRiccardo FoddeeLife Sciences Publications Ltdarticlepartial EMTcolon cancerphenotypic plasticityMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	partial EMT colon cancer phenotypic plasticity Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	partial EMT colon cancer phenotypic plasticity Medicine R Science Q Biology (General) QH301-705.5 Andrea Sacchetti Miriam Teeuwssen Mathijs Verhagen Rosalie Joosten Tong Xu Roberto Stabile Berdine van der Steen Martin M Watson Alem Gusinac Won Kyu Kim Inge Ubink Harmen JG Van de Werken Arianna Fumagalli Madelon Paauwe Jacco Van Rheenen Owen J Sansom Onno Kranenburg Riccardo Fodde Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
description	Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphological 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/β-catenin signaling, (2) a broad spectrum of degrees of epithelial to mesenchymal transition (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 β-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.
format	article
author	Andrea Sacchetti Miriam Teeuwssen Mathijs Verhagen Rosalie Joosten Tong Xu Roberto Stabile Berdine van der Steen Martin M Watson Alem Gusinac Won Kyu Kim Inge Ubink Harmen JG Van de Werken Arianna Fumagalli Madelon Paauwe Jacco Van Rheenen Owen J Sansom Onno Kranenburg Riccardo Fodde
author_facet	Andrea Sacchetti Miriam Teeuwssen Mathijs Verhagen Rosalie Joosten Tong Xu Roberto Stabile Berdine van der Steen Martin M Watson Alem Gusinac Won Kyu Kim Inge Ubink Harmen JG Van de Werken Arianna Fumagalli Madelon Paauwe Jacco Van Rheenen Owen J Sansom Onno Kranenburg Riccardo Fodde
author_sort	Andrea Sacchetti
title	Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
title_short	Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
title_full	Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
title_fullStr	Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
title_full_unstemmed	Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
title_sort	phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/edd28e2414b842c4998587deaa94f069
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Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

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