snapshot: the epithelial-mesenchymal transition · snapshot: the epithelial-mesenchymal transition...
TRANSCRIPT
162 Cell 145, April 1, 2011 ©2011 Elsevier Inc. DOI 10.1016/j.cell.2011.03.029 See online version for legend and references.
Snap
Shot:
The E
pit
helia
l-M
ese
nch
ymal
Tra
nsi
tion
Jona
than
P. S
leem
an3,
4 an
d J
ean
Pau
l Thi
ery2,
3
1 IM
CB
and
Exp
erim
enta
l The
rap
eutic
s C
entr
e, B
iop
olis
A*S
TAR
, 138
673
Sin
gap
ore
; 2 Can
cer
Sci
ence
Inst
itute
, 117
456
Sin
gap
ore
3 U
nive
rsity
of
Hei
del
ber
g, M
edic
al F
acul
ty M
annh
eim
, D-6
8167
Man
nhei
m, G
erm
any;
4 Kar
lsru
he In
stitu
te o
f Te
chno
log
y, P
ost
fach
364
0, 7
6021
Kar
lsru
he, G
erm
any
Lam
inin
5
TβR
ITβ
RI
TβR
II
Sna
il1/2
Zeb
1/2
Par3Par6
aPK
C
BM
Ps
BM
PR
1B
MP
R2
Pat
ched
Gro
wth
fact
ors
IL-6
JAG
2
JAM
p120-Cat
p53
Rho
A
Cd
c42
Rho
A
Rho
A
PD
GF
Cd
c42
Cd
c42
Glu
-tub
ulin
Rac
1
Par
6P
ar3
aPK
C
Cla
udin
JAM
Occ
lud
in
Cla
udin
Occ
lud
inZ
O3
ZO
1Z
O2
Act
in
IQG
AP
E-c
adhe
rin
Nec
tin
β-ca
t
β-ca
t β-ca
t
β-ca
t
β-ca
t
β-ca
t
Afa
din
F-ac
tin
Vin
culin
Xα
-Act
inin
Clip
170 Dyn
ein/
dyn
actin
com
ple
x
miR
-200
FOX
A1/
2
BA
SE
ME
NT
ME
MB
RA
NE
RO
CK
DD
R1
Co
llect
ive
cell
mig
ratio
np
190
Rho
GA
PD
AP
21P
GS
K3β
Rho
A
Rho
E
Myo
sin
light
chai
n
HIF
1/2
LoxL
2E
2.2
KLF
8
FOX
Q1
E47
GS
C
Twis
tS
nail1
/2
Sna
il1/2
Sm
ad2/
3
Hed
geho
g
ER
PAK
1
STA
T3
IL-6
R
PI3
KR
as
RTK
LIV
1A
KT
MA
PK
NF-
κB
NF-
κB
CS
L
Gli1
MTA
3
Zeb
1/2
miR
-205
miR
-200
miR
-205
E-c
adhe
rin
and
oth
erd
ow
nreg
ulat
ed g
enes
(see
box
A)
Up
reg
ulat
ed g
enes
(see
box
B)
E-c
adhe
rin
Des
mo
som
eC
yto
kera
tin
Gap
jun
ctio
n
Pla
kog
lob
inD
esm
op
laki
n
Bal
ance
dac
tivi
ties
Tig
ht
jun
ctio
n
EP
ITH
EL
IAL
ME
SE
NC
HY
MA
LM
ES
EN
CH
YM
AL
Ad
her
ens
jun
ctio
n
Sta
bili
zed
act
incy
tosk
elet
on A
pic
ob
asal
mic
rotu
bul
es
p120-Cat
p12
0-C
atK
aiso
p12
0-C
at
p12
0-C
at
GS
K3β
Dis
heve
lled
LRP
5/6
Friz
zled
Nec
tinA
fad
in
RTK
DD
R1
Col
lage
n 1
MM
Ps
NC
AM
N-c
ad PD
GFR
Tran
scrip
tion
Foca
lad
hesi
onfo
rmat
ion
Ad
here
nsju
nctio
nd
isas
sem
bly
Filo
pod
iaLa
mel
lipod
iaM
igra
tion
Inva
sion
EC
M r
emod
ellin
g
Foca
l ad
hesi
onas
sem
bly
and
tur
nove
r
Exa
mp
les
of
up
-re
gu
late
d g
en
es
TβR
IV
imen
tin
SM
AN
-cad
heri
nN
CA
MF
ibro
nect
inLa
min
ins
miR
-661
MM
Ps
Exa
mp
les
of
do
wn
-re
gu
late
d g
en
es
Tub
ulin
tyr
osi
ne li
gas
eC
laud
ins
Occ
lud
ins
ZO
1/Z
O3
Cru
mb
s3D
esm
op
laki
nC
onn
exin
43E
-cad
heri
nN
ecti
n-1
VE
-cad
heri
nC
yto
kera
tins
Co
llag
en I
, II
Oth
er
EM
T-a
sso
cia
ted
eff
ec
ts
Res
ista
nce
to s
enes
cenc
eR
esis
tanc
e to
ap
op
tosi
sT
hera
py
resi
stan
ceS
tem
ness
Cyt
oske
leto
nre
mod
elin
g
Mem
bra
neru
f�es
Loss
of
des
mos
omes
Mic
rote
ntac
les
Dis
soci
atio
n of
tight
junc
tions
Loss
of g
apju
nctio
ns
End
ocyt
osis
deg
rad
atio
n
Foca
l ad
hesi
onfo
rmat
ion In
crea
sed
TGF-β
sign
alin
g E-c
adhe
rind
egra
dat
ion
Bas
emen
t m
emb
rane
deg
rad
atio
n
EB
1
Nin
ein
p19
0R
hoG
AP
p19
0R
hoG
AP
Sm
urf1 α
-cat
Rap
1
FAK
FAK
FAK
Fyn
Rac
1b
Hyp
oxi
a
Rac
1
Rac
1
Rea
ctiv
eox
ygen
spec
ies
Pyk
2
ILK
AK
T
DA
B2
p13
0C
AS
α-c
at
A
B
Oth
er
EM
T-in
du
cin
g p
ath
wa
ys
ILE
IE
ndo
thel
in-A
rec
epto
r-P
I3K
TN
F-α
-NF
-κB
, A
ktH
yalu
roni
c ac
idC
OX
2-P
GE
2A
MF
PT
H(r
P)R
Bile
aci
ds
Nic
oti
neU
V ir
rad
iati
on
SC
FA
xl-G
as6
Ple
ctin
Wnt
FAK
Hak
ai
Rho
AP
rote
asom
e
CK
1 E
Par
3P
ar6
c-sr
c
c-sr
c
ZO
3Z
O1
ZO
2
Myo
sin
light
chai
n
Des
mo
som
e
P
Sm
ad2/
3 P
Sna
il1/2
P Pro
teas
ome
Pro
teas
ome
Pro
teas
ome
Pro
teas
ome
Pro
teas
ome
Pro
teas
ome
Pro
teas
ome
P-c
at
CK
1
β-ca
tP
Ub
Rho
A
Sna
il1/2
Rho
AP
rote
asom
eP
rote
asom
eP
rote
asom
e
Ub
FAK
ILK
P
P
Fyn
Fyn
P
TβββR
ITβ
RII
aPK
CPar
3P
ar6
P
β-ca
tc-
src
P
Inte
gri
nα
6β4
Inte
gri
nα
6β4
Des
mo
gle
inD
esm
og
lein
Des
mo
colli
nD
esm
oco
llin
NO
TCH
NO
TCH
Sm
ooth
ened
Sm
ooth
ened
TGF-β
TGF-β
Six
1
SnapShot: The Epithelial-Mesenchymal TransitionJonathan P. Sleeman3,4 and Jean Paul Thiery1,2
1IMCB and Experimental Therapeutics Centre, Biopolis A*STAR, 138673 Singapore2Cancer Science Institute, 117456 Singapore 3University of Heidelberg, Medical Faculty Mannheim, D-68167 Mannheim, Germany4Karlsruhe Institute of Technology, Postfach 3640, 76021 Karlsruhe, Germany
162.e1 Cell 145, April 1, 2011 ©2011 Elsevier Inc. DOI 10.1016/j.cell.2011.03.029
This SnapShot portrays important regulatory pathways and major cellular events that are activated during the transition from an epithelial to a mesenchymal morphology during development and disease. The cell on the left represents the epithelial state, whereas the central cell depicts transcriptional regulatory networks that orchestrate the process of epithelial-to-mesenchymal transition (EMT). The cell on the right illustrates some of the consequences of the activity of these networks that endow formerly epithelial cells with mesenchymal characteristics. Note that this overview does not take into account cell-type-specific regulation of EMT, and that not all illustrated mechanisms are obligate for EMT to occur. The temporal regulation of the EMT process is also not considered in this SnapShot.
The Epithelial PhenotypePolarized epithelial cells are typified by tight junctions, adherens junctions, desmosomes, and gap junctions. Junctional complexes not only act as mediators of polarized cell-cell contacts but also serve as anchor points for the actin cytoskeleton. Adherens junctions can additionally anchor apicobasal microtubule arrays, and through E-cadherin-DDR1 interactions are also involved in collective cell migration. Organization of the actin cytoskeleton, microtubule arrays, and cell-cell junctions is tightly coordinated in a mechanism that probably involves IQGAP, but the details remain to be investigated. Balanced regulation of the activities of RhoA (stress fibers), Cdc42 (filopodia), and Rac1 (lamellipodia) stabilizes the actin cytoskeleton and maintains the epithelial phenotype. Epithelial cells are tethered to the underlying basement membrane, for example through integrins. The repression of EMT-inducing transcriptional regulators (for example, through microRNAs), as well the activity of positively acting factors such as FOXA1/2, ensures that expression of key junctional proteins such as E-cadherin is maintained. Suppression of GSK3β also helps to maintain the epithelial phenotype.
Transcriptional Activation of EMTA variety of extracellular stimuli have the potential to induce EMT. A complex network of positively and negatively acting signal transduction mechanisms converge on the nucleus to downregulate genes required for the epithelial phenotype and to upregulate genes that specify mesenchymal characteristics. GSK3β and NF-κB play central roles in coordinating these pathways. Members of the Snail family of transcriptional regulators, namely Snail1 and Snail2, have emerged as a key regulatory node. The zinc finger transcription factors Zeb1 and Zeb2 also make a pivotal contribution to this regulation. EMT-inducing signals promote their expression, regulate their stability, and/or alter their subcellular location.
Loss of Epithelial and Acquisition of Mesenchymal CharacteristicsKey targets of the pathways that induce EMT include the adherens junction components E-cadherin and β-catenin. In addition to being transcriptionally downregulated and epigenetically switched off, E-cadherin can be proteolytically cleaved and targeted to endosomes for degradation. Proteosomal degradation of β-catenin destabilizes adherens junctions, whereas loss of E-cadherin can increase the free pool of β-catenin that can then enter the nucleus and modulate transcription. An important consequence of EMT-inducing transcriptional modulation as well as other pro-EMT processes is the loss of the junctional complexes that typify polarized epithelial cells. Enhanced activation of the GTPases Cdc42 and Rac1 and suppression of RhoA favor the formation of lamellipodia and filopodia, migration, and invasion. A variety of mechanisms promote the assembly and turnover of focal adhesions. Extensive cytoskeleton remodeling occurs, including switching from a predominantly cytokeratin to a vimentin-rich intermediate filament net-work. Detyrosination of tubulin promotes microtentacle formation. Proteolytic enzymes are produced that together with increased expression of extracellular matrix components serve to remodel the microenvironment surrounding the cells. Other properties endowed on cells undergoing EMT include resistance to apoptosis, senescence, and therapeutics and the acquisition of stemness characteristics.
Acknowledgments
This work was supported by a grant to J.P.S. from the European Union under the auspices of the FP7 collaborative project TuMIC, contract no. HEALTH-F2-2008-201662.
RefeRences
Casas, E., Kim, J., Bendesky, A., Ohno-Machado, L., Wolfe, C.J., and Yang, J. (2011). Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and me-tastasis. Cancer Res. 71, 245–254.
Chang, C.J., Chao, C.H., Xia, W., Yang, J.Y., Xiong, Y., Li, C.W., Yu, W.H., Rehman, S.K., Hsu, J.L., Lee, H.H., et al. (2011). p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol. 13, 317–323.
Hanahan, D., and Weinberg, R.A. (2011). Hallmark of cancers: the next generation. Cell 144, 646–674.
Hidalgo-Carcedo, C., Hooper, S., Chaudhry, S.I., Williamson, P., Harrington, K., Leitinger, B., and Sahai, E. (2011). Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat. Cell Biol. 13, 49–58.
Peinado, H., Olmeda, D., and Cano, A. (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415–428.
Schmalhofer, O., Brabletz, S., and Brabletz, T. (2009). E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 28, 151–166.
Thiery, J.P., and Sleeman, J.P. (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7, 131–142.
Thiery, J.P., Acloque, H., Huang, R.Y., and Nieto, M.A. (2009). Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890.
Whipple, R.A., Matrone, M.A., Cho, E.H., Balzer, E.M., Vitolo, M.I., Yoon, J.R., Ioffe, O.B., Tuttle, K.C., Yang, J., and Martin, S.S. (2010). Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement. Cancer Res. 70, 8127–8137.
Yilmaz, M., and Christofori, G. (2009). EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28, 15-33.