Abstract
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.
Highlights
Cancers of epithelial origin such as breast, prostate, pancreas, lung, and colon carcinomas are thought to develop from normal tissues through a multistep sequence of genetic events from benign precursor lesions to increasingly more malignant stages
We mainly focused on the HCT116 and SW480 lines as they are representative of the two main colon cancer subtypes earmarked by microsatellite instability (MIN) and chromosomal instability (CIN; known as microsatellite stable [MSS]), respectively (Lengauer et al, 1997)
Colon cancer provides a unique example for this conundrum: it is well-e stablished that a sequence of gene mutations underlies the adenoma-c arcinoma sequence at the primary site, no alterations have been identified in genes potentially able to underlie local invasion and distant metastasis
Summary
Cancers of epithelial origin such as breast, prostate, pancreas, lung, and colon carcinomas are thought to develop from normal tissues through a multistep sequence of genetic events from benign precursor lesions to increasingly more malignant stages. This is exemplarily illustrated by the adenoma-carcinoma sequence in colon cancer where a stepwise buildup of genetic alterations in specific oncogenes and tumor suppressor genes underlies tumor initiation and progression (Fearon and Vogelstein, 1990). Notwithstanding these ground rules, a very broad spectrum of molecular and cellular routes underlies EMT and the resulting phenotypic plasticity in a context-d ependent fashion (Cook and Vanderhyden, 2020)
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