Mathematical Modeling of Plasticity and Heterogeneity in EMT.

  title={Mathematical Modeling of Plasticity and Heterogeneity in EMT.},
  author={Shubham Tripathi and Jianhua Xing and Herbert Levine and Mohit Kumar Jolly},
  journal={Methods in molecular biology},
The epithelial-mesenchymal transition (EMT) and the corresponding reverse process, mesenchymal-epithelial transition (MET), are dynamic and reversible cellular programs orchestrated by many changes at both biochemical and morphological levels. A recent surge in identifying the molecular mechanisms underlying EMT/MET has led to the development of various mathematical models that have contributed to our improved understanding of dynamics at single-cell and population levels: (a) multi-stability… 

Understanding the Complex Milieu of Epithelial-Mesenchymal Transition in Cancer Metastasis: New Insight Into the Roles of Transcription Factors

This review critically examines the roles of TFs as drivers of molecular rewiring that lead to tumour initiation, progression, EMT, metastasis, and colonisation, and discusses the interaction of various signalling molecules and effector proteins with these factors.

Transcriptional and post-transcriptional control of epithelial-mesenchymal plasticity: why so many regulators?

A perspective on the fundamental question of whether it is really feasible that so many regulators play important roles and if so, what does this tell us about EMT and more generally, the genetic machinery that controls complex biological processes.

Identifying inhibitors of epithelial–mesenchymal plasticity using a network topology-based approach

It is shown that the ability to exhibit phenotypic plasticity correlates positively with the number of positive feedback loops in a given network, elucidating the importance of network topology in enabling phenotyping plasticity.

SNAIL driven by a feed forward loop motif promotes TGFβ induced epithelial to mesenchymal transition

System modelling and analysis of the devised network displayed interesting dynamic behavior, systems response to various inputs stimulus, providing a better understanding of p53/MDM2 dependent TGF-β induced Epithelial to Mesenchymal Transition.

The Mathematics of Phenotypic State Transition: Paths and Potential

This review discusses both the generalized physical principles and associated mathematical models developed to understand phenotypic state transition and the opportunities to connect these two approaches and the limitations of the current understanding and mathematical methods.

Mechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors

The focus of this review is on the mechanisms governing metabolic heterogeneity in breast cancer, which allows subtyping of cancers and further metabolic heterogeneity occurs within the same tumor mass thought of as “microenvironmental metabolic nesting”.

The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

A 30-year span of relevant literature is summarized, delineating the EndoMT process in particular, key signaling pathways, and the underlying regulatory networks involved in CVD.

Volumetric compression develops noise-driven single-cell heterogeneity.

A paradigm of how mechanical stimulations impact cell-fate determination by altering transcription dynamics is demonstrated, which shows a distinct path that the ecology and evolution of cancer interplay with their physical microenvironments from the view of mechanobiology and systems biology.

Epithelial-to-Mesenchymal Transition in Fibrosis: Concepts and Targeting Strategies

The aim of this mini review is to recapitulate the most recent concepts in the EMT field and to summarize the different strategies which have been exploited to target EMT in fibrotic disorders.



Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability

A non-linear hysteretic response of E-cadherin repression during TGFβ-induced EMT that is controlled by the strength of the miR-200s/ZEBs negative feedback loop and enhances metastasis is characterized.

TGF-β–induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops

Experimental and computational analyses identify multiple cell populations during the epithelial-to-mesenchymal transition and provide experimental confirmation for a model of cascading switches in phenotypes associated with TGF-β1–induced EMT of MCF10A cells that involves two double-negative feedback loops.

Stability of the hybrid epithelial/mesenchymal phenotype

The results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be ‘metastable’, and strengthen the emerging notion that partialEMT, but not necessarily a complete E MT, is associated with aggressive tumor progression.

Topography of epithelial–mesenchymal plasticity

A topographic map underlying epithelial–mesenchymal transitions is constructed using a combination of numerical simulations of a Boolean network model and the analysis of bulk and single-cell gene expression data, revealing a multitude of metastable hybrid phenotypic states.

EMT and MET: necessary or permissive for metastasis?

This work focuses on epithelial-mesenchymal plasticity in metastatic dissemination and proposes alternative mechanisms for successful dissemination and metastases beyond the traditional EMT-MET view.

Towards elucidating the connection between epithelial–mesenchymal transitions and stemness

Using a specially devised theoretical framework to investigate the dynamics of the LIN28/let-7 system, it is shown that it can operate as a three-way switch similar to the three- way operation of the miR-200/ZEB circuit that allows for the existence of a hybrid epithelial/mesenchymal (E/M) phenotype.

Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype

A mechanism-based theoretical model is devised that links cell–cell communication via Notch-Delta-Jagged signalling with the regulation of EMT and offers possible mechanistic insights into the role of Jagged in tumour progression, and offers a framework to investigate the effects of other microenvironmental signals during metastasis.

An Ovol2-Zeb1 Mutual Inhibitory Circuit Governs Bidirectional and Multi-step Transition between Epithelial and Mesenchymal States

This work has identified epithelial cells that naturally exist in an intermediate state with bidirectional differentiation potential, and found the balance between EMT-promoting and -inhibiting factors to be critical in achieving and selecting between intermediate states.