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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/61461 |
| _version_ | 1811199227405008896 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T01:45:31Z |
| format | Article |
| id | doaj.art-edd28e2414b842c4998587deaa94f069 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:45:31Z |
| publishDate | 2021-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-edd28e2414b842c4998587deaa94f0692022-12-22T03:53:06ZengeLife Sciences Publications LtdeLife2050-084X2021-05-011010.7554/eLife.61461Phenotypic plasticity underlies local invasion and distant metastasis in colon cancerAndrea Sacchetti0Miriam Teeuwssen1Mathijs Verhagen2https://orcid.org/0000-0003-3126-8379Rosalie Joosten3Tong Xu4Roberto Stabile5Berdine van der Steen6Martin M Watson7Alem Gusinac8Won Kyu Kim9Inge Ubink10Harmen JG Van de Werken11https://orcid.org/0000-0002-9794-1477Arianna Fumagalli12Madelon Paauwe13Jacco Van Rheenen14Owen J Sansom15https://orcid.org/0000-0001-9540-3010Onno Kranenburg16Riccardo Fodde17https://orcid.org/0000-0001-9839-4324Department of Pathology, Erasmus MC, Rotterdam, NetherlandsDepartment of Pathology, Erasmus MC, Rotterdam, NetherlandsDepartment of Pathology, Erasmus MC, Rotterdam, NetherlandsDepartment of Pathology, Erasmus MC, Rotterdam, NetherlandsDepartment of Pathology, Erasmus MC, Rotterdam, NetherlandsDepartment of Pathology, Erasmus MC, Rotterdam, NetherlandsDepartment of Otorhinolaryngology, Head and Neck Surgery, Erasmus University Medical Center, Erasmus MC, Rotterdam, NetherlandsDepartment of Pathology, Erasmus MC, Rotterdam, NetherlandsDepartment of Pathology, Erasmus MC, Rotterdam, NetherlandsNatural Product Research Center, Korea Institute of Science and Technology, Gangneung, Republic of KoreaDepartment of Surgical Oncology, Cancer Centre, University Medical Centre Utrecht, Utrecht, NetherlandsCancer Computational Biology Center and Department of Urology; Erasmus University Medical Center, Rotterdam, NetherlandsPrincess Máxima Center for Pediatric Oncology, Utrecht, NetherlandsCancer Research UK Beatson Institute, Glasgow, United KingdomDepartment of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, NetherlandsCancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow, United KingdomDepartment of Surgical Oncology, Cancer Centre, University Medical Centre Utrecht, Utrecht, NetherlandsDepartment of Pathology, Erasmus MC, Rotterdam, NetherlandsPhenotypic 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.https://elifesciences.org/articles/61461partial EMTcolon cancerphenotypic plasticity |
| spellingShingle | 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 eLife partial EMT colon cancer phenotypic plasticity |
| title | 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_short | Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer |
| title_sort | phenotypic plasticity underlies local invasion and distant metastasis in colon cancer |
| topic | partial EMT colon cancer phenotypic plasticity |
| url | https://elifesciences.org/articles/61461 |
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