Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

Jolly, Mohit Kumar; Tripathi, Satyendra Chandra; Somarelli, Jason A.; Hanash, Samir M.; Levine, Herbert

doi:10.1002/1878-0261.12084

Cited by 68 publications

(58 citation statements)

References 133 publications

(191 reference statements)

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“…Contrary to this, for the phase {HL, LH, HH}, the relative stability of the HH state was much larger than that of HL or LH states (FIG 3E inset). The HH state can be thought of as a "hybrid" adipocyte/hepatocyte state, similar to those observed in other tristable cell-fate decision networks [47,50,51]. This result, together with similar observations for the tetrastable phase (FIG S3I), emphasizes that a hybrid adipocyte-like state of hepatocytes (i.e.…”

Section: Multiple Stable States (Phenotypes) Can Co-exist Giving Rissupporting

confidence: 81%

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

Sahoo

Singh

Chakraborty

et al. 2020

Preprint

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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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Section: Multiple Stable States (Phenotypes) Can Co-exist Giving Rissupporting

confidence: 81%

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

Sahoo

Singh

Chakraborty

et al. 2020

Preprint

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“…This model includes the following interactions: (i) mutual repression between E-cadherin and TBX2, (ii) inhibition of NRAGE (neurotrophin receptor-interacting melanoma antigen) by E-cadherin (Kumar et al, 2011), and (iii) inhibition of anchorage-independent growth by the TBX2 complex, which is promoted in the presence of NRAGE (42). Such interconnected regulatory loops can often obviate an intuitive understanding of the emergent outcomes of these interactions (44). Thus, mechanism-based mathematical models can be a powerful tool for both helping explain previous experimental observations, and for making novel predictions to guide future experimental design (45).…”

Section: Resultsmentioning

confidence: 99%

E-cadherin represses anchorage-independent growth in sarcomas through both signaling and mechanical mechanisms

Jolly

Ware

et al. 2018

Preprint

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42E-cadherin, an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining 43 adherens junctions, regulating migration and invasion, and mediating intracellular signaling. 44 Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) and 45 correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is 46 prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin 47 expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly 48 understood. Here, by combining mathematical models with wet-bench experiments, we identify 49 the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional 50 consequences. Unlike in carcinomas, E-cadherin overexpression in sarcomas does not induce a 51 mesenchymal-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-52 independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts 53 to downregulate phosphorylated CREB (p-CREB) and the transcription factor, TBX2, to inhibit 54 anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of 55 E-cadherin on p-CREB levels and restores sensitivity to anchorage-independent growth in 56 sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also 57 strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, 58 our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing 59 anchorage-independent growth. 60 61 62 63 64 65 66 67 68 69 70 71Sarcomas -deadly cancers that arise from tissues of a mesenchymal lineage -are highly 72 aggressive, with five year survival rates of just 66% (1). Despite their mesenchymal origin, some 73 sarcomas undergo phenotypic plasticity in which they gain "epithelial-like" traits (2)(3)(4). While 74 this transition to a more epithelial-like state is now being recognized as a feature of multiple 75 subtypes of soft tissue sarcoma and osteosarcoma (2)(3)(4), there are also a number of sarcoma 76 subtypes that are classically known to exhibit epithelioid features pathologically, including 77 synovial sarcoma (5), epithelioid sarcoma (6), and adamantinoma (7). One might expect the 78 acquisition of epithelial-like traits to be of little relevance in mesenchymal tumors, yet that is not 79 the case. Phenotypic plasticity is clinically important in sarcoma patients: Sarcoma patients 80 whose tumors express epithelial-like biomarkers have improved outcomes relative to patients 81 with more "mesenchymal-like" tumors (2)(3)(4)8). 82 Phenotypic plasticity observed in sarcomas is reminiscent of the phenomenon of 83 epithelial plasticity in carcinomas. Epithelial plasticity refers to reversible transitions between 84 epithelial and mesenchymal phenotypes. In carcinomas, the phenotypic transition to a more 85 mesenchymal-like state via an epithelial-mesenchyma...

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“…Additionally, the model presented here is phenomenological; we do not infer the mechanisms by which an Allee effect may be occurring such as in [37,38], nor do we explicitly develop a model of subpopulation interactions as had been done in [6]. Future work will focus on investigating the molecular and cellular mechanisms for an Allee effect and developing a model of heterotypic subpopulation interactions that also considers phenotypic plasticity [67][68][69][70].…”

Section: Discussionmentioning

confidence: 99%

Cancer cell population growth kinetics at low densities deviate from the exponential growth model and suggest an Allee effect

et al. 2019

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Most models of cancer cell population expansion assume exponential growth kinetics at low cell densities, with deviations to account for observed slowing of growth rate only at higher densities due to limited resources such as space and nutrients. However, recent preclinical and clinical observations of tumor initiation or recurrence indicate the presence of tumor growth kinetics in which growth rates scale positively with cell numbers. These observations are analogous to the cooperative behavior of species in an ecosystem described by the ecological principle of the Allee effect. In preclinical and clinical models, however, tumor growth data are limited by the lower limit of detection (i.e., a measurable lesion) and confounding variables, such as tumor microenvironment, and immune responses may cause and mask deviations from exponential growth models. In this work, we present alternative growth models to investigate the presence of an Allee effect in cancer cells seeded at low cell densities in a controlled in vitro setting. We propose a stochastic modeling framework to disentangle expected deviations due to small population size stochastic effects from cooperative growth and use the moment approach for stochastic parameter estimation to calibrate the observed growth trajectories. We validate the framework on simulated data and apply this approach to longitudinal cell proliferation data of BT-474 luminal B breast cancer cells. We find that cell population growth kinetics are best described by a model structure that considers the Allee effect, in that the birth rate of tumor cells increases with cell number in the regime of small population size. This indicates a potentially critical role of cooperative behavior among tumor cells at low cell densities with relevance to early stage growth patterns of emerging and relapsed tumors.

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Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

Cited by 68 publications

References 133 publications

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

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

E-cadherin represses anchorage-independent growth in sarcomas through both signaling and mechanical mechanisms

Cancer cell population growth kinetics at low densities deviate from the exponential growth model and suggest an Allee effect

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