gene transcription via interactions with signaling mediators in addition to its cell adhesive functions. For example, E-cadherin directly
interacts with EGF receptors (EGFR) to influence downstream
MAP kinase signaling [106], and epidermal junctional tension
mediated by E-cadherin controls EGFR localization to restrict
signaling activity, thereby allowing polarized tight junction formation [107]. Feedback between junction assembly and downstream
signaling activity may thus be central to ensuring appropriate control over establishment of the epithelial state.
7 Conclusions
MET events are likely to be as pervasive as EMT during development and adult tissue homeostasis, yet our understanding of MET
mechanisms is comparably limited. This is likely in part due to a
paucity of models with which to interrogate MET. It is now recognized that MET is a critical and initiating event during reprogramming of somatic cells to pluripotency [108, 109], and that
sequential EMT-MET events are likely to govern differentiation
of pluripotent stem cells to a variety of somatic cell types in vitro
[110, 111]. Remarkably, changes in cell shape enforced by seeding
on micropatterned plates induced MET-like changes in fibroblasts
and enhanced reprogramming [112], indicating possible roles for
mechanotransduction in determining the epithelial state. These
models will help to shed further light on the various control
mechanisms that cells use to suppress and establish epithelial features. Importantly, the advent of human pluripotent stem cell
derived organoid models, in which cells recapitulate complex developmental events to establish diverse tissue fates, provides a wealth
of opportunities for studying EMT and MET events in more complex systems [113]. Organoids retain many three-dimensional features of tissues in vivo that are likely to be critical in determining
fate during differentiation. Furthermore, the emergence of highthroughput methods to investigate genome-wide epigenetic status
of developing cells will shed further light on chromatin-level control of EMT and MET events. Finally, MET is frequently dysregulated in pathological processes, highlighting the need for a better
understanding of this process to design better therapeutic
approaches for disease, including fibrosis due to aberrant wound
healing, and cancer metastasis [56, 114].
Acknowledgments
Funding: Work in the Ro ¨per lab is supported by the Medical
Research Council (file reference number U105178780 and
BSF30).
Mechanisms of MET in Development and Cancer
55
interacts with EGF receptors (EGFR) to influence downstream
MAP kinase signaling [106], and epidermal junctional tension
mediated by E-cadherin controls EGFR localization to restrict
signaling activity, thereby allowing polarized tight junction formation [107]. Feedback between junction assembly and downstream
signaling activity may thus be central to ensuring appropriate control over establishment of the epithelial state.
7 Conclusions
MET events are likely to be as pervasive as EMT during development and adult tissue homeostasis, yet our understanding of MET
mechanisms is comparably limited. This is likely in part due to a
paucity of models with which to interrogate MET. It is now recognized that MET is a critical and initiating event during reprogramming of somatic cells to pluripotency [108, 109], and that
sequential EMT-MET events are likely to govern differentiation
of pluripotent stem cells to a variety of somatic cell types in vitro
[110, 111]. Remarkably, changes in cell shape enforced by seeding
on micropatterned plates induced MET-like changes in fibroblasts
and enhanced reprogramming [112], indicating possible roles for
mechanotransduction in determining the epithelial state. These
models will help to shed further light on the various control
mechanisms that cells use to suppress and establish epithelial features. Importantly, the advent of human pluripotent stem cell
derived organoid models, in which cells recapitulate complex developmental events to establish diverse tissue fates, provides a wealth
of opportunities for studying EMT and MET events in more complex systems [113]. Organoids retain many three-dimensional features of tissues in vivo that are likely to be critical in determining
fate during differentiation. Furthermore, the emergence of highthroughput methods to investigate genome-wide epigenetic status
of developing cells will shed further light on chromatin-level control of EMT and MET events. Finally, MET is frequently dysregulated in pathological processes, highlighting the need for a better
understanding of this process to design better therapeutic
approaches for disease, including fibrosis due to aberrant wound
healing, and cancer metastasis [56, 114].
Acknowledgments
Funding: Work in the Ro ¨per lab is supported by the Medical
Research Council (file reference number U105178780 and
BSF30).
Mechanisms of MET in Development and Cancer
55