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.
-
Single cell 3' RNA sequencing of 6 Belgian colorectal cancer patientsNCBI Gene Expression Omnibus, GSE144735.
-
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.
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
© 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.
Metrics
-
- 4,181
- views
-
- 606
- downloads
-
- 49
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
eLife 10:e61461.
https://doi.org/10.7554/eLife.61461
Further reading
-
- Cancer Biology
- Cell Biology
Bestrophin isoform 4 (BEST4) is a newly identified subtype of the calcium-activated chloride channel family. Analysis of colonic epithelial cell diversity by single-cell RNA-sequencing has revealed the existence of a cluster of BEST4+ mature colonocytes in humans. However, if the role of BEST4 is involved in regulating tumour progression remains largely unknown. In this study, we demonstrate that BEST4 overexpression attenuates cell proliferation, colony formation, and mobility in colorectal cancer (CRC) in vitro, and impedes the tumour growth and the liver metastasis in vivo. BEST4 is co-expressed with hairy/enhancer of split 4 (HES4) in the nucleus of cells, and HES4 signals BEST4 by interacting with the upstream region of the BEST4 promoter. BEST4 is epistatic to HES4 and downregulates TWIST1, thereby inhibiting epithelial-to-mesenchymal transition (EMT) in CRC. Conversely, knockout of BEST4 using CRISPR/Cas9 in CRC cells revitalises tumour growth and induces EMT. Furthermore, the low level of the BEST4 mRNA is correlated with advanced and the worse prognosis, suggesting its potential role involving CRC progression.
-
- Cancer Biology
Pancreatic cancer has the worst prognosis of all common tumors. Earlier cancer diagnosis could increase survival rates and better assessment of metastatic disease could improve patient care. As such, there is an urgent need to develop biomarkers to diagnose this deadly malignancy. Analyzing circulating extracellular vesicles (cEVs) using ‘liquid biopsies’ offers an attractive approach to diagnose and monitor disease status. However, it is important to differentiate EV-associated proteins enriched in patients with pancreatic ductal adenocarcinoma (PDAC) from those with benign pancreatic diseases such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN). To meet this need, we combined the novel EVtrap method for highly efficient isolation of EVs from plasma and conducted proteomics analysis of samples from 124 individuals, including patients with PDAC, benign pancreatic diseases and controls. On average, 912 EV proteins were identified per 100 µL of plasma. EVs containing high levels of PDCD6IP, SERPINA12, and RUVBL2 were associated with PDAC compared to the benign diseases in both discovery and validation cohorts. EVs with PSMB4, RUVBL2, and ANKAR were associated with metastasis, and those with CRP, RALB, and CD55 correlated with poor clinical prognosis. Finally, we validated a seven EV protein PDAC signature against a background of benign pancreatic diseases that yielded an 89% prediction accuracy for the diagnosis of PDAC. To our knowledge, our study represents the largest proteomics profiling of circulating EVs ever conducted in pancreatic cancer and provides a valuable open-source atlas to the scientific community with a comprehensive catalogue of novel cEVs that may assist in the development of biomarkers and improve the outcomes of patients with PDAC.
