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Review
. 2017 Jul;11(7):755-769.
doi: 10.1002/1878-0261.12083. Epub 2017 Jun 12.

EMT and MET: necessary or permissive for metastasis?

Mohit Kumar Jolly  1 , Kathryn E Ware  2 , Shivee Gilja  2 , Jason A Somarelli  2 , Herbert Levine  1
Affiliations
Review

EMT and MET: necessary or permissive for metastasis?

Mohit Kumar Jolly et al. Mol Oncol. 2017 Jul.

Abstract

Epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. These phenotypic transitions between states are not binary. Instead, carcinoma cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). While epithelial/mesenchymal plasticity has been observed preclinically and clinically, whether any of these phenotypic transitions are indispensable for metastatic outgrowth remains an unanswered question. Here, we focus on epithelial/mesenchymal plasticity in metastatic dissemination and propose alternative mechanisms for successful dissemination and metastases beyond the traditional EMT/MET view. We highlight multiple hypotheses that can help reconcile conflicting observations, and outline the next set of key questions that can offer valuable insights into mechanisms of metastasis in multiple tumor models.

Keywords: epithelial-to-mesenchymal transition; hybrid epithelial/mesenchymal; mesenchymal-to-epithelial transition; metastasis; phenotypic plasticity.

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Figures

Figure 1
Figure 1
Representing EMT as a multidimensional nonlinear process. (A) EMT phenotypic landscape may contain multiple axes (x1–x5). (B) Induction of EMT by different EMT‐TFs may drive epithelial cells into different regions on this multidimensional landscape (shown by different colored dots). There may be some overlap in the effect of more than one EMT‐TFs in regulation of one or more of these axes contributing to EMT, as can be realized by projecting this multidimensional space into two principal component axes (PCA).
Figure 2
Figure 2
Role of EMT‐TFs. (A) EMT‐TFs can act as catalysts of cellular plasticity. A catalyst reduces the activation energy (by an amount of ∆E) required for the progression of a reaction. (B) Phase diagram showing different types of motility that can be possible at varying levels of EMT‐TFs and/or mesenchymal markers, and cellular motility. Dotted lines represent phase separations.
Figure 3
Figure 3
Plasticity‐dependent and plasticity‐independent pathways to metastasis. (A) In MET‐dependent metastasis, post‐EMT‐like cancer cells upregulate invasive programs that facilitate dissemination and seeding (red curve). The invasive program comes at a cost; EMT induction leads to downregulation of proliferative potential (blue curve). Re‐establishment of an epithelial‐like phenotype via MET at the metastatic site awakens the proliferative potential necessary for the formation of macrometastases. (B) In MET‐independent metastasis, therapy, epigenetic reprogramming, acquisition of novel mutations, or other mechanisms induce a post‐EMT state that becomes fixed in a proliferationhigh/invasionhigh phenotype. Cells metastasizing via an MET‐independent pathway may be more aggressive, stem‐like, chemorefractory, and more likely to seed and re‐seed further metastases.
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