Mendez, Mario J

Weinberg, Seth H

English

VCU Scholars Compass

Virginia Commonwealth UniversityVCU Scholars CompassBiology and Medicine Through MathematicsConference 2018May 31st, 6:00 PM - 6:30 PMCritical parameters in a computational model ofTGF-beta-induced epithelial mesenchymaltransition.Mario J. MendezVirginia Commonwealth University, mendezmj@mymail.vcu.eduSeth H. WeinbergVirginia Commonwealth University, shweinberg@vcu.eduFollow this and additional works at: https://scholarscompass.vcu.edu/bammPart of the Life Sciences Commons, Medicine and Health Sciences Commons, and theNumerical Analysis and Scientific Computing CommonsThis Event is brought to you for free and open access by the Dept. of Mathematics and Applied Mathematics at VCU Scholars Compass. It has beenaccepted for inclusion in Biology and Medicine Through Mathematics Conference by an authorized administrator of VCU Scholars Compass. Formore information, please contact libcompass@vcu.edu.https://scholarscompass.vcu.edu/bamm/2018/thursday/11Critical parameters in a computational model of TGF-beta-induced epithelial mesenchymal transition Mario Jose Mendez, Seth Weinberg PhD. Epithelial to mesenchymal transition (EMT) is a fundamental biological process that plays a central role in embryonic development, tissue regeneration, and pathological conditions, such as cancer metastasis and cystic fibrosis. EMT is the transdifferentiation of an epithelial cell to a mesenchymal stem cell; losing the characteristic cell-cell adhesion of an epithelial cell and gaining the increased cell motility of a mesenchymal cell. Classically, EMT has been viewed as an all-or-none switch; however, recent work has demonstrated the existence of bistability in the system, with an intermediate or partial (pEMT) state that retains some characteristics of the primary epithelial state but also shows features of mesenchymal state. Prior work has demonstrated that transforming growth factor-beta (TGF-beta) is a major and potent inducer of this cellular transition. In our study, we used a mathematical model of the core regulatory network describing TGF-beta-induced EMT, which consists of coupled reversible and irreversible bistable switches.  We performed simulations to determine critical parameters that govern two key features of the EMT process: (1) hysteresis in the TGF-beta-dependence of the transition from epithelial to the pEMT states and (2) the reversibility of the pEMT to mesenchymal state transition. We found that the presence of hysteresis depended on critical properties of the microRNA-34 signaling pathway.  In contrast, we found that mesenchymal reversibility depended on properties of the endogenous TGF-beta production. Model predictions demonstrate that both the reversibility and sensitivity of TGF-beta-mediated EMT is governed by complex interactions between these coupled switches.   

Critical parameters in a computational model of TGF-beta-induced epithelial mesenchymal transition.

Virginia Commonwealth University
VCU Scholars Compass
Biology and Medicine Through Mathematics
Conference 2018
May 31st, 6:00 PM - 6:30 PM
Critical parameters in a computational model of
TGF-beta-induced epithelial mesenchymal
transition.
Mario J. Mendez
Virginia Commonwealth University, mendezmj@mymail.vcu.edu
Seth H. Weinberg
Virginia Commonwealth University, shweinberg@vcu.edu
Follow this and additional works at: https://scholarscompass.vcu.edu/bamm
Part of the Life Sciences Commons, Medicine and Health Sciences Commons, and the
Numerical Analysis and Scientific Computing Commons
This Event is brought to you for free and open access by the Dept. of Mathematics and Applied Mathematics at VCU Scholars Compass. It has been
accepted for inclusion in Biology and Medicine Through Mathematics Conference by an authorized administrator of VCU Scholars Compass. For
more information, please contact libcompass@vcu.edu.
https://scholarscompass.vcu.edu/bamm/2018/thursday/11
Critical parameters in a computational model of TGF-beta-
induced epithelial mesenchymal transition 
Mario Jose Mendez, Seth Weinberg PhD. 
Epithelial to mesenchymal transition (EMT) is a fundamental biological process that plays a central role 
in embryonic development, tissue regeneration, and pathological conditions, such as cancer metastasis 
and cystic fibrosis. EMT is the transdifferentiation of an epithelial cell to a mesenchymal stem cell; losing 
the characteristic cell-cell adhesion of an epithelial cell and gaining the increased cell motility of a 
mesenchymal cell. Classically, EMT has been viewed as an all-or-none switch; however, recent work has 
demonstrated the existence of bistability in the system, with an intermediate or partial (pEMT) state 
that retains some characteristics of the primary epithelial state but also shows features of mesenchymal 
state. Prior work has demonstrated that transforming growth factor-beta (TGF-beta) is a major and 
potent inducer of this cellular transition. In our study, we used a mathematical model of the core 
regulatory network describing TGF-beta-induced EMT, which consists of coupled reversible and 
irreversible bistable switches.  We performed simulations to determine critical parameters that govern 
two key features of the EMT process: (1) hysteresis in the TGF-beta-dependence of the transition from 
epithelial to the pEMT states and (2) the reversibility of the pEMT to mesenchymal state transition. We 
found that the presence of hysteresis depended on critical properties of the microRNA-34 signaling 
pathway.  In contrast, we found that mesenchymal reversibility depended on properties of the 
endogenous TGF-beta production. Model predictions demonstrate that both the reversibility and 
sensitivity of TGF-beta-mediated EMT is governed by complex interactions between these coupled 
switches.   


https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=1217&amp;context=bamm

Critical parameters in a computational model of TGF-beta-induced epithelial mesenchymal transition.

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