N-cadherin as a key regulator of collective cell migration in a 3D environment.

2012·1.1 MB·English

by  Shih, Wenting

COMMENTARY
CellAdhesion&Migration6:6,513–517;November/December2012;G2012LandesBioscience
N-cadherin as a key regulator of collective cell migration
in a 3D environment
Wenting Shih and Soichiro Yamada*
DepartmentofBiomedicalEngineering;UniversityofCalifornia,Davis;Davis,CAUSA
Cell migration is a critical step of earlieststudyincellmigrationofprecardiac
normal developmental processes mesoderm cell clusters of a chick embryo
and disease progression. Often, migrat- suggested the importance of cell-cell junc-
ing cells interact and maintain contact tions for cohesive cell movement.1 The
with neighboring cells. However, the underlying mechanism of cell-cell adhesion
precise roles of cell-cell adhesion in cell issupportedbyalargecollectionofcell-cell
migration have thus far been poorly adhesion proteins,2 which in turn provides
defined. Often in aggressive cancers, N- the selective cell-to-cell interactions neces-
cadherinisprominentlyupregulated,yet, saryforcellrearrangementintissues.3While
these highly motile cells have limited the detailed mechanisms of single cell
cell-cell adhesion when plated on a stiff migrationhavebeenexplored,littleisknown
2Dsubstrate.But,thesamecellsina3D aboutthemechanismsandregulationofcell-
matrix migrate as a multicellular cluster. celladhesionduringcollectivecellmigration.
This new observation suggests that N- Traditional strategies for studying cell
cadherin-mediatedcell-celladhesionsup- migration have focused on examining
ports cell interactions between migrating migratingcells on a two-dimensional (2D)
cells in a more physiologically relevant surface. Although flattened cells on a 2D
3D matrix, but not on a 2D substrate. surface provide better visualization for fine
While N-cadherin is an integral part of cytoskeletalstructures,thesestiffsubstrates
neuralsynapses,theectopicexpressionof arenotanidealsurfaceforstudyingcell-to-
N-cadherin in transformed epithelial cellinteractionsofmigratingcells.Ona2D
cells plays an equally important part in substrate, highly migratory cells frequently
initiating pro-migratory signaling, and detach and scatter from their neighbors
providing strong yet flexible cell cohe- (Fig.1),4whereasina3Dmatrix,thesame
sion essential for persistent cell migra- cellsmaintaincell-cellcontactsandmigrate
tion in a 3D matrix. The 3D cell collectively as a cell cluster (Fig.1),5 This
Keywords: cell migration, 3D matrix, migration analysis for studying cell-to- unique collective cell morphology is likely
cell-cell adhesion, N-cadherin, cell interactions exposes the roles of N- duetothesoft3Dmatrix(relativetoastiff
Epithelial-to-mesenchymal transition cadherin in multicellular migration, and coverslip) that dissipates or absorbs the
revealsnovelinsightsintocellmigration- traction force exerted on the matrix. With
Submitted: 07/05/12
dependent normal and pathological effective cellular traction force reduced in
Revised: 08/07/12 processes. thesoftmatrix(e.g.,collagenorMatrigelTM
Accepted: 08/08/12 matrix) migrating cells are thus prevented
from moving away from each other. By
http://dx.doi.org/10.4161/cam.21766
Introduction examiningcellmigrationinamorephysio-
*Correspondenceto:SoichiroYamada;
logical 3D matrix, the roles of cell-cell
Email:[email protected]
All multicellular organisms depend on cell adhesion in this collective cell movement
movement as a driving force for embryo- areexposed.
Commentaryto:ShihW,YamadaS.N-cadherin-
mediatedcell-celladhesionpromotescell genesis,tissueremodelandrepair.Migrating The question remains as to which mole-
migrationinathree-dimensionalmatrix.JCellSci cells maintain contact with neighboring cules or types of cell-cell junctions facilitate
2012;125:3661–70;PMID:22467866;http://dx.doi. cells, which is thought to provide a spatial cell-to-cell interactions between migratory
org/10.1242/jcs.103861
cue for collective cell migration. Even the epithelial cells. During developmental
www.landesbioscience.com CellAdhesion&Migration 513
Figure1.Cellmigrationphenotypeon2Dsurfaceandin3Dmatrix.Whilemigratingcellsdetachfrequentlyfromneighboringcellsonacollagen-coated
2Dsurface,migratingcellsmaintaincell-cellcontactsina3Dcollagenmatrix.Thecellsarehepatocytegrowthfactor(HGF)-treatedMDCKepithelialcells
thathaveundergoneacompleteEMT.Whitearrowheadtracksthepositionofamigratingcell.Scalebar,20mm.Timeinminutes.
processesandcancermetastasis,epithelialcells single cells in the 3D matrix have a round (MAPK-ERK) pathway (Fig.2B),11 a sig-
alter their gene expression profile and lose shape and do not migrate.5 This is naling pathway that correlates with MMP
theirtypicalepithelialmorphologytoadopta consistent with previous studies which productionandcellinvasion.12Inaddition,
more invasive, mesenchymal phenotype, a showed that transient expression of N-cadherin-expression suppresses Akt3
process known as epithelial-to-mesenchymal N-cadherin in breast carcinoma cells expression and phosphorylation, which
transition(EMT).Thismorphologicaltrans- increases cell motility and invasiveness in promotes cell migration,13 although the
formation is accompanied by the loss of a Boyden chamber,9,10 and the increased detailedpathwayisstillunclear.
typical epithelial cell-cell junctions and the motility observed in various breast The cytoplasmic domain of cadherins
downregulation of E-cadherin, but in its carcinoma cell lines is independent regulates Rho GTPases, and this regulation
place, the upregulation of N-cadherin. This of E-cadherin levels.10 Interestingly, this is cadherin type-specific. Unlike the forma-
cadherin switching is not limited to E-to-N immobile phenotype of N-cadherin-defi- tion of E-cadherin junctions that activates
cadherin and epithelial cells.6 For cientcellsisnotduetothelackofcell-cell Rac1 and cdc42,14,15 the formation of N-
example, neural crest cells lose their adhesion since calcium removal disrupts cadherin junctions activates RhoA, but not
typical N-cadherin expression, and cell-cell adhesion between N-cadherin Rac1 and cdc42 in myoblasts.16 Further-
instead express cadherin-6B and cad- expressing invasive cells in 3D matrix, more, previous studies have shown that
herin-7 when entering a more migratory yettheindividualcellscontinuetomigrate p120-cateninintheN-cadherincomplexof
state.7 Therefore, depending on whether independently of their neighboring cells.5 fibroblasts associates with a RhoA-specific
it is natively or ectopically expressed, the This suggests that disruption of cell-cell GTPaseactivatingprotein,p190RhoGAP,17
same cadherins may play different roles in adhesion does not completely halt cell while b-catenin in the postsynaptic density
embryonic development, cell differenti- migrationandthattherolesofN-cadherin of neurons interacts with RICS (RhoGAP
ation and cancer cell invasion. In cancer, in cell migration is not limited to involved in the b-catenin-N-cadherin and
theswitchfrom E-cadherin toN-cadherin supporting cell-to-cell interactions. NMDA receptor signaling), a GTPase-
expression is a hallmark of cancer pro- WhichdomainofN-cadherinisimport- activating protein specific to cdc42 and
gression and is often observed in meta- ant for pro-migratory signaling? The exo- Rac1 GTPases (Fig.2B).18 Since these
static tumors.6,8 Therefore, this newly genous expression of the cytoplasmic or previousstudiesoftenfocusedonspecialized
upregulated N-cadherin emerged as a extracellulardomainofN-cadherininduces cells that natively express N-cadherin, and
potential regulator of collective cancer cellmigrationinN-cadherindeficientcells only analyzed cells on a 2D substrate,
cell migration. (Fig.2A),5 suggesting that both the cyto- additional tests are necessary to verify
plasmic and extracellular domain promote whether highly invasive post EMT cells in
N-Cadherin-Mediated cell migration, but presumably through a3DenvironmentusesimilarRhoGTPase
Pro-Migratory Signaling independent mechanisms. Previous studies regulations.
have shown that the N-cadherin extracel- One key function of N-cadherin is
The role of N-cadherin in collective cell lular domain directly interacts with the establishing cell polarity by limiting
migration is not limited to adhesive roles. fibroblast growth factor (FGF) receptor to protrusive activity at cell-cell contacts,
Forexample,N-cadherin-deficientcellsdo regulate the mitogen-activated protein whichiscriticalforpersistent,multicellular
not form cell clusters, and the resultant kinase-extracellular signal regulated kinase movement. In a 3D matrix, disruption of
514 CellAdhesion&Migration Volume6Issue6
Figure2.N-cadherin-mediatedcell-celladhesionregulatescollectivecellmigration.(A)Cellclustersadoptdifferentmigrationphenotypesdependingon
thestrengthofN-cadherinmediatedcell-celladhesion.IntheabsenceofN-cadherin-mediatedcell-celladhesion(e.g.,theextracellulardomaindeleted
N-cadherinmutantexpressingcells),thecellsaremigratorybutremainsinglecells.Withweakcell-celladhesion(e.g.,thecytoplasmicdeletedN-cadherin
mutantcells),migratorycellsoftenformcellclustersbutcell-cellinteractionsaretransient.Inwildtypecells,cell-celladhesionisstrongenoughto
minimizecellscattering,butdynamicenoughtosupportcellintercalationwithincellclusters.TheexpressionofanN-cadherin-a-cateninchimera
inducesstrongcell-celladhesionthatpreventscellintercalation,butpromotessupracellularmovementoftheentirecluster.(B)Modeldepicting
differentpathwaysthroughwhichN-cadherincanregulatecellmigration.N-cadherin4thextracellulardomainhasbeenshowntointeractwithfibroblast
growthfactorreceptor(FGFreceptor),whichisinvolvedinthepro-migratoryMAPK/ERKpathway.N-cadherincytoplasmicdomaininteractswithbinding
partnerssuchasb-catenin(b-cat),whichinteractswitha-catenin(a-cat),amoleculethatcanbindandorganizetheactinnetwork.Furthermore,
N-cadherincytoplasmicdomainmayberegulatingcellmigrationthroughtheregulationofGTPaseactivity.N-cadherinbindingpartner,b-cateninalso
bindsRICS,aGTPaseactivatingproteinforcdc42andRac1.Or,N-cadherinbindingpartner,p120-catenin(p120-cat)bindsp190RhoGAP(p190),whichisa
GTPaseactivatingproteinforRhoA.
N-cadherin-mediated cell-cell adhesion The Regulation structuresthroughitsregulationoftheactin
results in the dissociation of cell clusters, of N-Cadherin-Mediated cytoskeleton. For example, when the N-
and the resultant individual cells extend Cell-Cell Adhesion cadherin-deficient cells are rescued with an
protrusions in multiple directions causing N-cadherinanda-cateninfusionproteinto
them to no longer migrate together in The physical adhesion between migratory artificially promote N-cadherin and actin
a single direction.5 Similarly, during cells must be strong to withstand external interaction,theserescuedcellsdonotmove
Xenopus embryogenesis, neuralcell cluster forces exerted by neighboring migratory or intercalate within the cell cluster com-
dissociation by calcium removal or cells. N-cadherin knockdown cells expres- pared with cells expressing wild-type N-
N-cadherin inhibition results in cells singtheextracellulardomainofN-cadherin cadherin (Fig.2A).5 If this N-cadherin
extendingprotrusionsontopofeachother, areabletoformsmallclusters,butthecells chimera is providing a stable cadherin-actin
the loss of Rac1 activity at the cell’s free frequently dissociate from cell clusters linkage,thenthedynamicsofthecadherin-
edgeandsignificantlyreducedefficiencyof compared with wild-type cells in a 3D actin interactions play a crucial role in cell
chemotactic migration.19 Consistent with matrix (Fig.2A).5 This suggests that intercalation. Previous in vitro biochemical
this, hippocampal neurons lacking aN- although the extracellular domain of analysis has shown that a-catenin does not
catenin, an actin regulator in the cadherin N-cadherinmaybesufficientforinitialcell bind the E-cadherin complex and the actin
complex, results in hyperactive filopodia adhesionbetweencells,buttheN-cadherin cytoskeleton simultaneously,21 but rather
protrusionsfromthespineheadsincontact cytoplasmic domain is important for bindsand regulates actin filament organiza-
with axons.20 These data indicate that strengthening the adhesion, presumably tionindependentlyofitsinteractionwiththe
cadherin mediated cell-cell adhesion may by regulating the actin cytoskeleton in the cadherin complex (Fig.2B).22 Therefore, a
be required for the suppression of mem- vicinityofN-cadherinjunctions(Fig.2B). simple static model of the cadherin-actin
braneprotrusion,thuspromotingcollective The cadherin cytoplasmic domain is the linkage via a-catenin is unrealistic and
cell polarization, and migration of the key regulator of strength and structural the cadherin-actin interaction is most likely
clusterinthesamedirection. integrityofcell-celljunctionsinmulticellular highlydynamicinlivecells.
www.landesbioscience.com CellAdhesion&Migration 515
It is possible that this dynamic cad- generates a unique actin network in collec- heterogeneous extracellular matrices will
herin-actin linkage may be temporally tivelymigratingcells. better mimic the physiological environ-
strengthened to withstand intermittent Intransformedepithelial cells, clustered ment and more realistic cell movement.
forces exerted by neighboring cells. For cells organize actin into bundles of stress From recent studies, it is becoming
example, E-cadherin-mediated cell-cell fibers that are aligned parallel to the evident that cell-cell adhesion proteins
junctions stiffen in response to applied direction of cell elongation and traction such as N-cadherin contribute more than
shearstressandthismechano-regulationof force, and appear to terminate at cell-cell simplyanadhesiverolebetweenneighbor-
cadherin junctions depends on vinculin.23 junctions.5 N-cadherin-mediated cell-cell ingcells.TheextensiverolesofN-cadherin
This mechano-sensitive property of cad- junctions may be important for connect- include signaling migration, regulating
herin junctions may be in part regulated ing these actin bundles and coordinating strong yet dynamic cell-cell junctions and
via a conformational change in a-catenin. the actin organization continuously organizing actin throughout cells in a
Under a force-free condition (e.g., in the across multiple cells within a cluster. cluster. However, the precise mechanistic
presenceofmyosinIIinhibitor),a-catenin Consistently, a supracellular organization pathways behind how N-cadherin contri-
isinaclosed conformation thatmasksthe of actin has also been described in other butes to these diverse roles remain to be
vinculin binding site, whereas under a systemsincludingradialactinfibers,which examined.Forexample,howcellsgenerate
force-bearing condition, a-catenin isin an form a network across epithelial sheets,32 the supracellular actin organization and
open conformation with an accessible and cortical actin that extends across use such actin network for coordinated
vinculin binding domain.24 Accordingly, multiplemelanomacellswithinacluster.33 movement of the cell cluster. Also, the
vinculin localization to cell-cell junctions In addition, for the collective motion of specific molecules involved in the
depends on the external forces.24,25 cell clusters on a 2D substrate, myosin II N-cadherin pro-migration signaling path-
Another potential force-responsive regu- activity at the sites of cell-cell adhesion way need to be uncovered.
lating protein at cadherin junctions is is downregulated.34 This unique actin- Elucidating the mechanisms of collective
zyxin.26 In a 3D matrix, zyxin localizes to myosin II organization across multiple cell migration is important because metasta-
the sites of force-bearing N-cadherin junc- cells is likely important for the coordina- sizingcancercellssuchasmammarycarcino-
tions between transformed epithelial cells tionofcontractileforcesandcellmigration mas migrate as elongated multicellular
(Fig.3). Zyxin is recruited to actin stress as a collective group in a 3D matrix. chains.35-37Thiscollectivetumorcellinvasion
fibers upon uniaxial stretching of cells on a maybeaneffectivestrategyfortransportinga
compliantsubstrate27orthroughtheapplica- Future Perspectives sizablenumberofcellstoanewlocationfor
tion of external force on the cell dorsal colonization, thus facilitating metastasis.
surface.28,29 Furthermore, zyxin responds to Cell migration studies have traditionally Consistentwiththis,carcinomachainmigra-
notonlyexternalforcesaspreviouslyshown used single cells on 2D surfaces, leaving tion is often associated with high metastatic
but also internal actin-myosin contractile themechanismsofmulticellularmigration capacityandapoorprognosis.38Similarly,in
forces.30 In addition, stretch-induced actin in 3D matrix less well understood. melanomaexplantsculturedina3Dmatrix,
polymerization at focal adhesion sites is However, research trends are progressing collective chain migration occurred most
dependentonzyxinanditsinteractionwith toward the use of 3D matrices, which frequentlyinsamplesderivedfrommelanoma
the actin-binding Ena/VASP proteins.31 expose types of cell movement that are tumors, which had penetrated deeper in the
Therefore, in response to forces exerted by not readily accessible on 2D substrates. tissue,andposedahighrisktothepatient.33
migratory cells, the mechano-sensitive cad- Current 3D cell migration studies involve Although cell-cell adhesion molecules are
herin complex may be regulating its inter- theuseofmatriceswitharelativelysimple thought to be important for mediating
action with the actin cytoskeleton through and homogeneous composition. Future junctions within the cell clusters, the precise
various adaptor proteins, which in turn investigations in the development of roles of cell-cell adhesion in multicellular
migration are only beginning to emerge.
Studying multicellular migration will, not
only improve our understanding of normal
developmental processes, but also provide
insights into how to better target and
minimizepathologicalcellmigration,thereby
improving current strategies for suppressing
tumorcellinvasionandmetastasis.
Acknowledgments
The Yamada laboratory is supported by a
Figure3.Zyxinaccumulatesatsitesofforce-bearingN-cadherinmediatedcell-celljunctionsin Beckman Young Investigator Award, a
transformedepithelialcellsmigratingina3Dmatrix.Zyxin-GFPexpressingMDCKcellsare NIHEUREKAGM094798,andthefund
embeddedinacollagengel,andimagedusingaconfocalmicroscope.Zyxinaccumulatesasfocal
from the University of California Cancer
adhesion-likepunctaatcell-cellcontactsina3Dmatrix.Scalebar,10mm.
Research Coordinating Committee.
516 CellAdhesion&Migration Volume6Issue6
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