EMT/MET plasticity in cancer and Go-or-Grow decisions in quiescence: the two sides of the same coin?

Abstract

Epithelial mesenchymal transition (EMT) and mesenchymal epithelial transition (MET) are genetic determinants of cellular plasticity. These programs operate in physiological (embryonic development, wound healing) and pathological (organ fibrosis, cancer) conditions. In cancer, EMT and MET interfere with various signalling pathways at different levels. This results in gross alterations in the gene expression programs, which affect most, if not all hallmarks of cancer, such as response to proliferative and death-inducing signals, tumorigenicity, and cell stemness. EMT in cancer cells involves large scale reorganisation of the cytoskeleton, loss of epithelial integrity, and gain of mesenchymal traits, such as mesenchymal type of cell migration. In this regard, EMT/MET plasticity is highly relevant to the Go-or-Grow concept, which postulates the dichotomous relationship between cell motility and proliferation. The Go-or-Grow decisions are critically important in the processes in which EMT/MET plasticity takes the central stage, mobilisation of stem cells during wound healing, cancer relapse, and metastasis. Here we outline the maintenance of quiescence in stem cell and metastatic niches, focusing on the implication of EMT/MET regulatory networks in Go-or-Grow switches. In particular, we discuss the analogy between cells residing in hybrid quasi-mesenchymal states and G_Alert, an intermediate phase allowing quiescent stem cells to enter the cell cycle rapidly.

Keywords: Cancer; Cancer stem cells; EMT; MET; Quiescence; Stem cells.

Fig. 1

EMT pathways are embedded in signalling networks in cancer cells. Various signalling pathways exemplified on the top promote EMT by activating EMT-TFs. A Transcriptional regulation of epithelial-mesenchymal plasticity. In cells undergoing EMT, EMT-TFs repress transcription of epithelial genes encoding components of various epithelial structures, such as polarity complexes and adherens junctions, and activate the expression of mesenchymal genes. MET-inducing transcription factors (MET-TFs) repress transcription of mesenchymal markers, activate epithelial transcription programs, and act in double-negative feedback loops involving EMT-TFs. B EMT-inducing signals are modified by EMT-TFs/microRNA loops. EMT-TFs and microRNAs form interrelated double-negative feedback loops which affect expression levels of certain components of EMT-inducing signalling network. C EMT-TFs physically interact with components of signalling pathways forming complexes that in turn influence target genes. D EMT/MET mutually regulate alternative splicing. EMT-TFs regulate expression of epithelial (e.g., ESRP1/2) or mesenchymal (e.g., QKI) splicing factors, which in turn determine formation of epithelial- or mesenchymal-specific protein isoforms required for the accomplishment of EMT or MET programs. E Expression of metabolic genes of glycolysis and oxidative phosphorylation pathways are controlled by EMT-TFs

Fig. 2

An overview of “Go-or-Grow” concept. Main orchestrators of CDK activity namely p27^KIP1, p21^CIP1, and p57^KIP2 inhibit proliferation (”Grow”) and activate migration (”Go”) via direct/indirect interactions with the components of cell cycle machinery and EMT-TFs network (see text for details)

Fig. 3

A parallel between G_Alert and E/M hybrid states of cells. The same factors such as N-cadherin, TGFβ, IL6, GAS6/AXL, p27^KIP1 and SNAIL2 are implicated in both stem cell quiescence and EMT/MET equilibrium