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

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)

Competing models on TGF-β induced EMT

1) Cascading binary switches (VT: CBS)

6

Tian et al., Biophys. J. 105:1079 (2013)

Activation

Inhibition

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

Two models make qualitatively different predictions

8

VT: CBS model prediction

Rice: TCS model prediction

TGF-β TGF-β

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)

mRNA/miRNA levels show clear two-step behavior

10

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

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

Two models make qualitatively different predictions

13

VT: CBS model prediction

Rice: TCS model prediction

TGF-β TGF-β

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)

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

The temporal EMT dynamics also shows two-step behavior

16Zhang, Tian, et al., Sci Signaling, 7, ra91 (2014)

Summary and Summary and ongoingongoing effortsefforts

17

TGF-β1 induced EMT in MCF10 A cells is regulated by a

cascade of binary switches.

Analogous landscape picture

18

Have we seen the whole elephant?

19

We may discover more complex cell phenotype landscapes

Epigenetic modification also play essential role in EMT

20Zhang, et. al., Phys. Rev. Lett., 112:068101 (2014)

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)

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

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: xing1@pitt.edu

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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