Emerging Concepts of Hybrid Epithelial-to-Mesenchymal Transition in Cancer Progression

Abstract

Epithelial mesenchymal transition (EMT) is a complex process through which epithelial (E) cells lose their adherens junctions, transform into mesenchymal (M) cells and attain motility, leading to metastasis at distant organs. Nowadays, the concept of EMT has shifted from a binary phase of interconversion of pure E to M cells and vice versa to a spectrum of E/M transition states preferably coined as hybrid/partial/intermediate EMT. Hybrid EMT, being a plastic transient state, harbours cells which co-express both E and M markers and exhibit high tumourigenic properties, leading to stemness, metastasis, and therapy resistance. Several preclinical and clinical studies provided the evidence of co-existence of E/M phenotypes. Regulators including transcription factors, epigenetic regulators and phenotypic stability factors (PSFs) help in maintaining the hybrid state. Computational and bioinformatics approaches may be excellent for identifying new factors or combinations of regulatory elements that govern the different EMT transition states. Therapeutic intervention against hybrid E/M cells, though few, may evolve as a rational strategy against metastasis and drug resistance. This review has attempted to present the recent advancements on the concept and regulation of the process of hybrid EMT which generates hybrid E/M phenotypes, evidence of intermediate EMT in both preclinical and clinical setup, impact of partial EMT on promoting tumourigenesis, and future strategies which might be adapted to tackle this phenomenon.

Keywords: collective migration; epithelial/mesenchymal phenotype; hybrid/partial EMT; metastasis; phenotypic stability factor; stemness.

Figure 1

Hybrid E/M cells as a transition state of epithelial mesenchymal transition (EMT). E, M and E/M specific markers and characteristics during different transition states. Loss of cellular adherens of E cells allow them to undergo EMT and are released into the blood circulations as circulating tumour cells (CTCs). CTCs were found to exhibit hybrid E/M phenotypes which can transform into M forms and induce metastasis through M-to-E transition (MET) at distant sites.

Figure 2

Regulation of hybrid EMT by various factors. The hybrid E/M transition state (CD104+CD44^hi) between the E (CD104+CD44^lo) and M (CD104-CD44^hi) phenotypes are regulated by various factors including micro RNAs (miR), long non-coding RNAs (lncRNAs), other epigenetic regulators, regulatory TFs of hybrid EMT, phenotypic stability factors (PSFs) and other regulators of hybrid EMT.