Abstract
Simple SummaryMetastasis is a complex dynamic multistep process; however, our knowledge is still limited. Very few circulating tumor cells (CTCs) are metastatic precursor cells and represent the intermediate stage of metastasis. Epithelial–mesenchymal plasticity (EMP) has crucial roles in tissue development and homeostasis, and also in metastasis formation. In this study, we explored the EMP phenotype of a unique series of CTC lines, obtained from a patient with colon cancer during the disease course and treatment, by detecting markers involved in the epithelial–mesenchymal and mesenchymal–epithelial (MET) transitions. This study shows that these colon CTC lines have acquired only few mesenchymal features to migrate and intravasate, whereas an increase of MET-related markers was observed, suggesting that metastasis-competent CTCs need to revert quickly to the epithelial phenotype to reinitiate a tumor at a distant site.Metastasis is a complicated and only partially understood multi-step process of cancer progression. A subset of cancer cells that can leave the primary tumor, intravasate, and circulate to reach distant organs are called circulating tumor cells (CTCs). Multiple lines of evidence suggest that in metastatic cancer cells, epithelial and mesenchymal markers are co-expressed to facilitate the cells’ ability to go back and forth between cellular states. This feature is called epithelial-to-mesenchymal plasticity (EMP). CTCs represent a unique source to understand the EMP features in metastatic cascade biology. Our group previously established and characterized nine serial CTC lines from a patient with metastatic colon cancer. Here, we assessed the expression of markers involved in epithelial–mesenchymal (EMT) and mesenchymal–epithelial (MET) transition in these unique CTC lines, to define their EMP profile. We found that the oncogenes MYC and ezrin were expressed by all CTC lines, but not SIX1, one of their common regulators (also an EMT inducer). Moreover, the MET activator GRHL2 and its putative targets were strongly expressed in all CTC lines, revealing their plasticity in favor of an increased MET state that promotes metastasis formation.
Highlights
Cancer is the second leading cause of death in the world, and metastasis is the major cause of cancer-related death [1,2]
To investigate Sine oculis homeobox 1 (SIX1) expression in the nine circulating tumor cells (CTCs) lines, we compared the microarray expression data obtained in these lines and in the primary HT-29 and metastatic SW620 colon adenocarcinoma cell lines (Figure S2)
SIX1 expression was significantly downregulated in HT-29 cells (4.29-fold) and in all nine CTC lines (3.92-fold) compared with SW620 cells (Figure 1A)
Summary
Cancer is the second leading cause of death in the world, and metastasis is the major cause of cancer-related death [1,2]. Metastasis is a dynamic and complex process in which some cancer cells dissociate from the primary tumor, gain migratory potential, and enter the blood circulation to reach and colonize specific distant organs, where they may find favorable conditions to grow and form a secondary tumor [4]. CTCs reflect the tumor burden, and harbor similar mutations as the primary tumor and mutations specific of these more aggressive cells They highlight the presence of minimal residual disease, and can be used to detect a metastatic recurrence [5]. To intravasate and join the bloodstream, tumor cells must lose epithelial polarity and gain migratory capacity to pass through the basement membrane This process is called epithelial-to-mesenchymal transition (EMT) [9]. For the purposes of this manuscript, EMP is defined as the co-existence of epithelial and mesenchymal markers in CTCs to allow moving from EMT to MET
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