Measuring and Modelling the Epithelial Mesenchymal Hybrid State in Cancer: Clinical Implications

Abstract

The epithelial-mesenchymal (E/M) hybrid state has emerged as an important mediator of the elements of cancer progression facilitated by epithelial mesenchymal plasticity (EMP). We review here the evidence for the presence and prognostic potential of E/M hybrid state in carcinoma, modelling predictions and validations studies to demonstrate stabilised E/M hybrid intermediates along the spectrum of EMP, and computational approaches for characterising and quantifying EMP phenotypes, with particular attention to the emerging realm of single-cell approaches through RNA sequencing and protein-based approaches.

Diversity of Epithelial-Mesenchymal Phenotypes in Circulating Tumour Cells from Prostate Cancer Patient-Derived Xenograft Models

“…This hybrid state has been shown to be more metastatic than epithelial or mesenchymal states [ 20 , 22 , 23 ]. EMP may thus promote the metastatic cascade by enabling the cells to adjust to changing microenvironments and enhance cell survival in the circulation and at distant sites [ 24 ].…”

Mechanical Pressure Driving Proteoglycan Expression in Mammographic Density: a Self-perpetuating Cycle?

“…Durtotaxis can be explored using a clutch model in which local stick-slip dynamics of cell-matrix adhesions are integrated at the tissue level through cell-cell junctions [91], a cellular Potts model extended to include the mechanical response of focal adhesions [92], and discrete models where the position of an individual cell updates at a rate dependent on the stiffness at its current position [93]. Furthermore, the role of ECM density and stiffness on cancer cell invasion [94][95][96] EMT [97,98], and stress giving rise to proliferative disorders and avascular tumour growth can also be explored with models [99].…”

The role of mechanical interactions in EMT

“…If at any time the chemical concentration drops below the threshold the cell loses its invasive phenotype, which it can only regain once the chemical concentration increases above C . The ability of the cell to gain and lose its invasive phenotype is associated with epithelial-mesenchymal plasticity [14]. The second part of the process is where the boundary cell, once it acquires the invasive phenotype, detaches from the tissue [42] in [ t, t + d t ) with probability ω ( c N ( t )) d t where c N ( t ) is the chemical concentration in the boundary cell N at time t .…”

“…Mathematical models have proven to be a powerful tool to improve our understanding of EMT by providing a conceptual framework in which to integrate and analyse experimental data and make testable predictions, some of which have since been experimentally validated, for example, the existence of the epithelial/mesenchymal hybrid state [3, 4, 12, 13, 14, 15] and waves of temporal cell-cell detachments [16, 17]. Experimental and modelling studies are typically performed either at the single-cell level, by considering regulatory networks [3, 12, 13], or at the population-level, for example where cell populations are modelled with lattice based frameworks and the inclusion of cell-cell communication results in spatial heterogeneity [18].…”