Controlling Stochasticity in Epithelial-Mesenchymal Transition Through Multiple Intermediate Cellular States

Overview

Journal Discrete Continuous Dyn Syst Ser B

Date 2018 Mar 3

PMID 29497351

Citations 12

Authors

Catherine Ha Ta

Qing Nie

Tian Hong

Affiliations

Soon will be listed here.

Abstract

Epithelial-mesenchymal transition (EMT) is an instance of cellular plasticity that plays critical roles in development, regeneration and cancer progression. Recent studies indicate that the transition between epithelial and mesenchymal states is a multi-step and reversible process in which several intermediate phenotypes might coexist. These intermediate states correspond to various forms of stem-like cells in the EMT system, but the function of the multi-step transition or the multiple stem cell phenotypes is unclear. Here, we use mathematical models to show that multiple intermediate phenotypes in the EMT system help to attenuate the overall fluctuations of the cell population in terms of phenotypic compositions, thereby stabilizing a heterogeneous cell population in the EMT spectrum. We found that the ability of the system to attenuate noise on the intermediate states depends on the number of intermediate states, indicating the stem-cell population is more stable when it has more sub-states. Our study reveals a novel advantage of multiple intermediate EMT phenotypes in terms of systems design, and it sheds light on the general design principle of heterogeneous stem cell population.

Citing Articles

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Inference of Intercellular Communications and Multilayer Gene-Regulations of Epithelial-Mesenchymal Transition From Single-Cell Transcriptomic Data.

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References

Gaudet S, Spencer S, Chen W, Sorger P . Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis. PLoS Comput Biol. 2012; 8(4):e1002482. PMC: 3343095. DOI: 10.1371/journal.pcbi.1002482. View

Di Talia S, Skotheim J, Bean J, Siggia E, Cross F . The effects of molecular noise and size control on variability in the budding yeast cell cycle. Nature. 2007; 448(7156):947-51. DOI: 10.1038/nature06072. View

Lim W, Lee C, Tang C . Design principles of regulatory networks: searching for the molecular algorithms of the cell. Mol Cell. 2013; 49(2):202-12. PMC: 3664230. DOI: 10.1016/j.molcel.2012.12.020. View

Baulida J, Garcia de Herreros A . Snail1-driven plasticity of epithelial and mesenchymal cells sustains cancer malignancy. Biochim Biophys Acta. 2015; 1856(1):55-61. DOI: 10.1016/j.bbcan.2015.05.005. View

Chang H, Hemberg M, Barahona M, Ingber D, Huang S . Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature. 2008; 453(7194):544-7. PMC: 5546414. DOI: 10.1038/nature06965. View

Jolly M, Jia D, Boareto M, Mani S, Pienta K, Ben-Jacob E . Coupling the modules of EMT and stemness: A tunable 'stemness window' model. Oncotarget. 2015; 6(28):25161-74. PMC: 4694822. DOI: 10.18632/oncotarget.4629. View

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

Hong T, Watanabe K, Ta C, Villarreal-Ponce A, Nie Q, Dai X . An Ovol2-Zeb1 Mutual Inhibitory Circuit Governs Bidirectional and Multi-step Transition between Epithelial and Mesenchymal States. PLoS Comput Biol. 2015; 11(11):e1004569. PMC: 4640575. DOI: 10.1371/journal.pcbi.1004569. View

Shen Y, Shi C, Wei W, Yu W, Li W, Yang Y . The heterogeneity and dynamic equilibrium of rat embryonic stem cells. Cell Res. 2011; 21(7):1143-7. PMC: 3193490. DOI: 10.1038/cr.2011.98. View

10.

Zhang J, Tian X, Zhang H, Teng Y, Li R, Bai F . TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci Signal. 2014; 7(345):ra91. DOI: 10.1126/scisignal.2005304. View

11.

Ye X, Tam W, Shibue T, Kaygusuz Y, Reinhardt F, Eaton E . Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 2015; 525(7568):256-60. PMC: 4764075. DOI: 10.1038/nature14897. View

12.

Weston W, Zayas J, Perez R, George J, Jurecic R . Dynamic equilibrium of heterogeneous and interconvertible multipotent hematopoietic cell subsets. Sci Rep. 2014; 4:5199. PMC: 4047531. DOI: 10.1038/srep05199. View

13.

Lei J, Levin S, Nie Q . Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation. Proc Natl Acad Sci U S A. 2014; 111(10):E880-7. PMC: 3956188. DOI: 10.1073/pnas.1324267111. View

14.

Tyson J, Novak B . Functional motifs in biochemical reaction networks. Annu Rev Phys Chem. 2010; 61:219-40. PMC: 3773234. DOI: 10.1146/annurev.physchem.012809.103457. View

15.

Sosa M, Bragado P, Aguirre-Ghiso J . Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014; 14(9):611-22. PMC: 4230700. DOI: 10.1038/nrc3793. View

16.

Huang R, Wong M, Tan T, Kuay K, Ng A, Chung V . An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). Cell Death Dis. 2013; 4:e915. PMC: 3847320. DOI: 10.1038/cddis.2013.442. View

17.

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

18.

Hong T, Oguz C, Tyson J . A Mathematical Framework for Understanding Four-Dimensional Heterogeneous Differentiation of CD4+ T Cells. Bull Math Biol. 2015; 77(6):1046-64. PMC: 4474756. DOI: 10.1007/s11538-015-0076-6. View

19.

Tian X, Zhang H, Xing J . Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition. Biophys J. 2013; 105(4):1079-89. PMC: 3752104. DOI: 10.1016/j.bpj.2013.07.011. View

20.

Hart Y, Antebi Y, Mayo A, Friedman N, Alon U . Design principles of cell circuits with paradoxical components. Proc Natl Acad Sci U S A. 2012; 109(21):8346-51. PMC: 3361385. DOI: 10.1073/pnas.1117475109. View