Trends in Cell Biology
Volume 29, Issue 3, March 2019, Pages 212-226
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Review
EMT Transition States during Tumor Progression and Metastasis

https://doi.org/10.1016/j.tcb.2018.12.001Get rights and content

Highlights

EMT occurs through distinct intermediate states in vivo.

Distinct EMT transition states can be identified using cell surface markers and single-cell RNA-sequencing.

Distinct EMT transition states present different functions, with the hybrid EMT state presenting the highest metastatic potential.

Distinct EMT transition states present different gene expression and chromatin landscape.

Distinct EMT transition states are localized in different niches that regulate cell fate transitions.

Epithelial–mesenchymal transition (EMT) is a process in which epithelial cells acquire mesenchymal features. In cancer, EMT is associated with tumor initiation, invasion, metastasis, and resistance to therapy. Recently, it has been demonstrated that EMT is not a binary process, but occurs through distinct cellular states. Here, we review the recent studies that demonstrate the existence of these different EMT states in cancer and the mechanisms regulating their functions. We discuss the different functional characteristics, such as proliferation, propagation, plasticity, invasion, and metastasis associated with the distinct EMT states. We summarize the role of the transcriptional and epigenetic landscapes, gene regulatory network and their surrounding niche in controlling the transition through the different EMT states.

Section snippets

EMT Transition States

Epithelial–mesenchymal transition (EMT) is a cellular process in which cells lose their epithelial characteristics and acquire mesenchymal features. EMT has been associated with various tumor functions, including tumor initiation, malignant progression, tumor stemness, tumor cell migration, intravasation to the blood, metastasis, and resistance to therapy 1, 2, 3. EMT has long been viewed as a binary process with two distinct cell populations, epithelial and mesenchymal 1, 4, and is often

EMT in Mouse Cancer Models

Until recently, most studies on EMT were performed using cancer cell lines in vitro or by assessing pathological specimens of human cancers, precluding the assessment of the functional significance and the cellular plasticity of EMT in vivo. Moreover, due to the lack of expression of epithelial markers in full EMT, it is difficult to determine with high confidence whether cells expressing only mesenchymal markers correspond to tumor cells or to cancer associated fibroblasts. For these reasons,

EMT Transition States In Vivo

In HF derived SCCs presenting features of carcinosarcoma, EpCAM is expressed in a bimodal pattern in YFP+ tumor cells, suggesting that EMT may occur as a binary switch. However, a screen of a large panel of cell surface markers performed in these tumors revealed that EpCAM mesenchymal tumor cells were heterogeneous and expressed different levels of the cell surface markers CD106, CD61 and CD51 [9]. Combinatorial multicolor FACS analysis revealed that EpCAM mesenchymal tumor cells could be

Stemness and Plasticity of EMT Transition States

Cancer stem cells describe a population of tumor cells with increased tumorigenic potential that self-renew and differentiate into different types of tumor cells present in primary tumors. Cellular assays, including tumor transplantation, lineage tracing, and lineage ablation have been developed to assess tumor stemness [48]. EMT has been associated with tumor stemness by their increased tumor propagating potential following their transplantation into immunodeficient mice. Forced expression of

EMT Transition States and Metastasis

The role of EMT in metastasis has been recently debated and there are cancers that seem to metastasize without EMT. EMT was initially shown to promote metastasis by the demonstration that Twist1 silencing in breast cancer cell lines decreases lung metastasis [55]. In contrast, it was suggested that EMT was dispensable for metastasis due to the presence of metastasis in a mouse model of pancreatic tumors in which either Twist1 or Snai1 were deleted [56], or in a mouse mammary tumor model with

Microenvironment Associated with EMT Transition States

The phenotypic plasticity by which epithelial tumor cells that initially undergo EMT are able to revert to epithelial phenotype by MET at the distant site has been suggested to be regulated by the microenvironment [2]. Supporting this hypothesis, the different EMT populations are localized in distinct tumor regions associated with particular microenvironment in skin SCC and mammary tumors [9]. The composition of the different stromal components changes as tumor cells progress towards EMT, with

Gene Regulatory Network of EMT Transition States

The different EMT transitional states are associated with changes in the chromatin and transcriptional landscape of the cells that are mediated by gene regulatory networks (GRNs) that control the gene expression program specific of each state. Recent progresses have been made to define the enhancer logic and GRN that control the different EMT states.

Chromatin profiling using assay for transposase-accessible chromatin using sequencing (ATAC-seq) in HF derived SCCs combined with transcriptional

Concluding Remarks

The studies summarized in this review demonstrate that EMT is not a binary process, and different tumor cell populations presenting different degrees of EMT can be found in different cancers. These different populations present different functional properties and the hybrid EMT state is associated with increased metastatic potential.

Despite the progresses in the identification of the different EMT states and understanding the mechanisms regulating cell fate transition in tumors, there are still

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