A possible role for epigenetic feedback regulation in the dynamics of the epithelial–mesenchymal transition (EMT)

Jia, Wen; Deshmukh, Abhijeet; Mani, Sendurai A.; Jolly, Mohit Kumar; Levine, Herbert

doi:10.1088/1478-3975/ab34df

Cited by 85 publications

(79 citation statements)

References 51 publications

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“…moving from monostable epithelial region to a monostable mesenchymal region (Fig. 1B), and the timescale over which SNAIL levels are varied are commensurate with those over which EMT is observed [34, 35].…”

Section: Resultsmentioning

confidence: 89%

Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination

Sarkar

Sinha

Levine

et al. 2019

Preprint

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13In the vicinity of a tipping point, critical transitions occur when small changes in an input condition causes 14 sudden, large and often irreversible changes in the state of a system. Many natural systems ranging from 15 ecosystems to molecular biosystems are known to exhibit critical transitions in their response to stochastic 16 perturbations. In diseases, an early prediction of upcoming critical transitions from a healthy to a dis-17 ease state by using early warning signals is of prime interest due to potential application in forecasting 18 disease onset. Here, we analyze cell-fate transitions between different phenotypes (epithelial, hybrid epithe-19 lial/mesenchymal (E/M) and mesenchymal states) that are implicated in cancer metastasis and chemoresis-20 tance. These transitions are mediated by a mutually inhibitory feedback loop microRNA-200/ZEB driven 21 by the levels of transcription factor SNAIL. We find that the proximity to tipping points enabling these 22 transitions among different phenotypes can be captured by critical slowing down based early warning sig-23 nals, calculated from the trajectory of ZEB mRNA level. Further, the basin stability analysis reveals the 24 unexpectedly large basin of attraction for a hybrid E/M phenotype. Finally, we identified mechanisms that 25 can potentially elude the transition to a hybrid E/M phenotype. Overall, our results unravel the early warn- 26 ing signals that can be used to anticipate upcoming epithelial-hybrid-mesenchymal transitions. With the 27 emerging evidence about the hybrid E/M phenotype being a key driver of metastasis, drug resistance, and 28 tumor relapse; our results suggest ways to potentially evade these transitions, reducing the fitness of cancer 29 cells and restricting tumor aggressiveness. 30 Keywords: critical transition | indicators of critical slowing down | alternative stable states | epithelial-31 hybrid-mesenchymal transition | cancer biology 32 1 This article contains supplementary materials. 2 sudipta@iitrpr.ac.in 3 h.levine@northeastern.edu 4 mkjolly@iisc.ac.in 5 parthasharathi@iitrpr.ac.in Significance Statement 33Epithelial-hybrid-mesenchymal transitions play critical roles in cancer metastasis, drug resistance, and tumor 34 relapse. Recent studies have proposed that cells in a hybrid epithelial/mesenchymal phenotype may be more 35 aggressive than those on either end of the spectrum. However, no biomarker to predict upcoming transitions 36 has been identified. Here, we show that critical slowing down based early warning signals can detect sudden 37 transitions among epithelial, hybrid E/M, and mesenchymal phenotypes. Importantly, our results highlight 38 how stable a hybrid E/M phenotype can be, and how can a transition to this state be avoided. Thus, our 39 study provides valuable insights into restricting cellular plasticity en route metastasis. 40 Introduction 41Biological systems often display nonlinear dynamics and emergent complex behavior, and consequent multi-42 stability [1, 2]. This nonlinear behavior in many ...

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Section: Resultsmentioning

confidence: 89%

Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination

Sarkar

Sinha

Levine

et al. 2019

Preprint

Self Cite

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“…To test this feature, one can isolate a population of steatotic hepatocytes and observe if it can give rise to non-steatotic hepatocytes (implying reversibility) when cultured separately in vitro. The extent of reversibility can depend on various factors such as remodeling of the cellular microenvironment and/or epigenetics [74]. Thus, it would also be interesting to quantify the reversibility of a fatty liver phenotype as the disease progresses from NAFLD to a more inflammatory state, NASH [75].…”

Section: Discussionmentioning

confidence: 99%

Emergent properties of HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD

Sahoo

Singh

Chakraborty

et al. 2020

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Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of chronic liver disease in adults and children. It is characterized by excessive accumulation of lipids in the hepatocytes of patients without any excess alcohol intake. With a global presence of 24% and limited therapeutic options, the disease burden of NAFLD is increasing. Thus, it becomes imperative to attempt to understand the dynamics of disease progression at a systems-level. Here, we decode the emergent dynamics of underlying gene regulatory networks that have been identified to drive the initiation and progression of NAFLD. We have developed a mathematical model to elucidate the dynamics of the HNF4α-PPARγ gene regulatory network. Our simulations reveal that this network can enable multiple co-existing phenotypes under certain biological conditions: an adipocyte, a hepatocyte, and a "hybrid" adipocyte-like state of the hepatocyte. These phenotypes may also switch among each other, thus enabling phenotypic plasticity and consequently leading to simultaneous deregulation of the levels of molecules that maintain a hepatic identity and/or facilitate a partial or complete acquisition of adipocytic traits. These predicted trends are supported by the analysis of clinical data, further substantiating the putative role of phenotypic plasticity in driving NAFLD. Our results unravel how the emergent dynamics of underlying regulatory networks can promote phenotypic plasticity, thereby propelling the clinically observed changes in gene expression often associated with NAFLD.

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“…Cells induced to undergo EMT for shorter durations (~2-6 days) may revert to an epithelial state after withdrawal of the signal/stimulus. However, some cells exposed to EMT-inducing signals for longer durations (~10 days or more) may get 'locked' in a mesenchymal state, making EMT largely irreversible, at least for the timescale observed experimentally [11][12][13][14]. The possibility of an irreversible EMT is also supported by multiple phenomenological observations [15][16][17].…”

Section: Introductionmentioning

confidence: 89%

“…Multiple mechanisms have been proposed to explain the existence of a 'tipping point' -a time point beyond which continued treatment with EMT inducing signals can drive an irreversible EMT. These include self-stabilizing feedback loops [18][19][20][21] in the regulatory circuits for EMT/MET and/or epigenetic alterations [13,22,23]. However, similar investigations about the irreversibility of MET, or in other words, the resistance of epithelial cells to undergo EMT in response to EMT-inducing signals, remain to be done.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Jia

Tripathi

Chakraborty

et al. 2020

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Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

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A possible role for epigenetic feedback regulation in the dynamics of the epithelial–mesenchymal transition (EMT)

Abstract: Supplementary Information 1.Theoretical model for microRNA-based chimeric circuits In microRNA-based chimeric (MBC) circuits, microRNA(miR) molecules bind to the 3' UTR of an mRNA of the target protein in order to form a miR-mRNA complex. As a result, miRs can

Cited by 85 publications

References 51 publications

Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination

Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination

Emergent properties of HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

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