a cascade of bistableswitches controls tgf-β- induced ... · a cascade of bistableswitches...
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A Cascade of bistable switches controls TGF-β-
induced epithelial to mesenchymal transition
1
Jianhua Xing
Departments of Biological Sciences & Physics, Virginia Tech
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Epithelial-to-Mesenchymal Transition is a fundamental cellular process
4Human Embryo Cancer metastasis
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Several EMT phenotypes have been reported
5
Question: How are these EMT phenotypes generated?
Cancer metastasis
Circulating tumor cells
Yu et al., Science, 339:580 (2013)
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Competing models on TGF-β induced EMT
1) Cascading binary switches (VT: CBS)
6
Tian et al., Biophys. J. 105:1079 (2013)
Activation
Inhibition
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Competing models on EMT regulation
2) Ternary Chimera Switch (Rice: TCS)
7
Lu et al., PNAS, 110:18144 (2013)Existence of this self activation awaits for
experimental confirmation
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Two models make qualitatively different predictions
8
VT: CBS model prediction
Rice: TCS model prediction
TGF-β TGF-β
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TGF-β1 induced MCF10A cell EMT transition
0 ng/ml 0.5 ng/ml
9
2 ng/ml
Green: E-cadherin (Epithelial marker)
Red: Vimentin (Mesenchymal marker)
Blue: nucleus
Zhang, Tian, et al., Sci Signaling, 7, ra91 (2014)
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mRNA/miRNA levels show clear two-step behavior
10
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Flow cytometry data shows clear three phenotypes
0.5 ng/ml
4 ng/ml2 ng/ml
1 ng/ml0 ng/ml
EP
M
EP E
MM
Vim
en
tin
11
MM
P
E-cadherin
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Reversibility tests
0 ng/ml 0.5 ng/ml 2 ng/ml1 ng/ml
Vim
en
tin
TGF-β1
12
0 ng/mlE-cadherin
Vim
en
tin
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Two models make qualitatively different predictions
13
VT: CBS model prediction
Rice: TCS model prediction
TGF-β TGF-β
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Snail1
FSC
-A
0 ng/mlTGF-β1 0.5 ng/ml 1 ng/ml 4 ng/ml2 ng/ml
Snail1/Zeb1 measurements support the CBS model
E E+P E+P+M P+M M
14
E E+P E+P+M P+M M
Zeb1
FSC
-A
Zhang, Tian, et al., Sci Signaling, 7, ra91 (2014)
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Further theoretical analysis identifies several molecular
mechanisms for Snail/miR34 bistability
1. Nonlinearity from Snail1 binding to miR34 promoter
2. Ultra-sensitive-like motif with positive feedback
miRNA
mRNA
mRNA-miRNA
miRNA + small molecules
Small molecules
TF
15Tian, et al., in preparation
mRNA miRNA + small molecules
mRNA Small molecules
miRNA
kmiR
Tota
l m
RN
A
TF
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The temporal EMT dynamics also shows two-step behavior
16Zhang, Tian, et al., Sci Signaling, 7, ra91 (2014)
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Summary and Summary and ongoingongoing effortsefforts
17
TGF-β1 induced EMT in MCF10 A cells is regulated by a
cascade of binary switches.
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Analogous landscape picture
18
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Have we seen the whole elephant?
19
We may discover more complex cell phenotype landscapes
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Epigenetic modification also play essential role in EMT
20Zhang, et. al., Phys. Rev. Lett., 112:068101 (2014)
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Embryonic Stem Cells
(iPSC)
A central question we ask: how cells maintain a robustly stable yet
plastic phenotype?
21
How can an fertilized egg develop into over 200 cell types?
How can a cell maintain its type over generations?
How can a cell collectively revise its expression program during
a phenotypic transition?
CardiomyocytesFibroblasts
http://www.arthursclipart.org/medical/humanbody
/cell%20types.gif Wang, et al., Interface Focus, 4:20130068 (2014)
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Systems biology approaches are needed for complex cell
phenotypic transition processes
Mathematical modeling
Computer simulations
Experimental
studies, esp. single cell
22
Computer simulations
Theoretical analysis
studies, esp. single cell
and high throughput
techniques
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Xing labXing lab::Current: Dr Xiaojun TianHang ZhangAbhishek MukhopadhyayJingyu Zhang
AcknowledgementsAcknowledgements
CollaboratorCollaborator::Subbiah Elanekumaran (VT)Fan Bai (Peking University)Ruoyan Li (Peking University)Yue Teng (Beijing Institute of Microbiology and Epidemiology)
Financial support:
– The Thomas F. Jeffress and Kate Miller Jeffress Memorial Trust
– NSF Emerging Frontier Program
– NIGMS/DMS Mathematical Biology Program
– NIAID
– VT Fralin Institute
23
Current Xing lab website:
http://www.faculty.biol.vt.edu/xing/index.html
Email: [email protected]
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Dept of Computational & Systems Biology
The Xing lab will move to
24
Dept of Computational & Systems Biology
University of Pittsburgh
(http://www.csb.pitt.edu)
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