Tuning Collective Cell Migration by Cell–Cell Junction Regulation

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Peter Friedl1,2,3 and Roberto Mayor4

1Department of Cell Biology, Radboud University Medical Centre, Nijmegen 6525GA, The Netherlands 2David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 3Cancer Genomics Center, 3584 CG Utrecht, The Netherlands 4Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom Correspondence: [email protected]; [email protected]

Collective cell migration critically depends on cell–cell interactions coupled to a dynamic actin cytoskeleton. Important cell–cell adhesion receptor systems implicated in controlling collective movements include cadherins, immunoglobulin superfamily members (L1CAM, NCAM, ALCAM), Ephrin/Eph receptors, Slit/Robo, connexins and integrins, and an adaptive array of intracellular adapter and signaling proteins. Depending on molecular composition and signaling context, cell–cell junctions adapt their shape and stability, and this gradual junction plasticity enables different types of collective cell movements such as epithelial sheet and cluster migration, branching morphogenesis and sprouting, collective network migration, as well as coordinated individual-cell migration and streaming. Thereby, plasticity of cell–cell junction composition and turnover deﬁnes the type of collective movements in epithelial, mesenchymal, neuronal, and immune cells, and deﬁnes migration coordination, anchorage, and cell dissociation. We here review cell–cell adhesion systems and their functions in different types of collective cell migration as key regulators of collective plasticity.

ulticellular organisms form and maintain the basis of all polarized epithelia, vessels, mus- Mtheir bodies through the ability of individ- cle, neuronal tissue, as well as cell organization ual cells to adhere to neighbor cells by cell–cell in connective tissue. Dynamic cell–cell junc- junctions, which are mechanically both stable tions enable cells to change position relative to and flexible and secure cell position and func- their neighbors or as multicellular groups; they tion over time. Stable junctions anchor cells in are relevant during morphogenesis and phases their tissue niche and define cell–cell coopera- of tissue activation, for example, in response to tion and mechanical function such as contrac- injury or inflammation (Collins and Nelson tion or cell–cell signaling. These junctions are 2015). By regulating junction “fluidity,” the ag-

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P. Friedl and R. Mayor

gregate state and dynamics of cells can change nating their migration and transient clustering remarkably and, accordingly, alter collective with other leukocytes for signal exchange, functions (Collins and Nelson 2015; Park et al. which depends on very dynamic physical and 2016). chemical cell–cell interactions (Malet-Engra Depending on the cell type and activation et al. 2015). state, a range of adhesion receptor and cytoskel- By combining different adhesion systems in etal adaptor systems are involved in securing a modular manner in time and space, cells re- short- or long-lived, dynamic or stable cell– spond to extracellular triggers and tune their cell interactions. These include cadherins and levels of cell–cell cooperation. We here summa- protocadherins, immunoglobulin (Ig) super- rize the range of cell–cell junction types ex- family members, desmosomal and tight junc- pressed by different cell types, their morpholo- tion (TJ) proteins, as well as integrins, selectins, gies and kinetics, and implications for collective ephrin/eph receptors, and, likely, connexins, migration, anchorage, and cell dissociation. We which all directly or indirectly couple to the further review how different types of cell–cell- intracellular cytoskeleton and mediate distinct interaction-based dynamics and collective cell cell–cell adhesion types (Theveneau and Mayor migration are “tunable” and allow for adaptive 2012a; Collins and Nelson 2015). Controlled by strategies of cell movements for different phys- upstream signaling, each receptor type can un- iological and pathological contexts and discuss dergo context-dependent alteration in surface their implications for classifying collective and expression, ligand interaction, and cytoskeletal single-cell behaviors. coupling, and mediate a range of dedicated types of cell–cell coupling. CELL–CELL ADHESION SYSTEMS Many types of collective cell–cell behaviors depend on stable cell–cell anchorage to form Common to all adhesion systems is the require- layered cell sheets or complex forms of tissue ment for an initial interaction between trans- organization, including barrier function medi- membrane cell-surface receptors on adjacent ated by epithelia and endothelia toward the cells, which usually are followed by the recruit- extra- and intracorporal spaces, intercellular ment of intracellular adaptor and cytoskeletal signaling network functions as in neuronal net- proteins. This complex regulates the shape and works, or large-scale contraction and force gen- mechanical stability of the adhesion junction, eration as in muscle or purse–string contrac- its interaction with intracellular effectors, and tion of epithelia (Tada and Heisenberg 2012; adhesion-mediated activation of downstream Sunyer et al. 2016). Most dynamic multicellular signaling pathways. Typically, cells use several functions, which depend on long-lived cell–cell complementary adhesion systems in parallel, junctions lasting hours to days or weeks, can be resulting in a cell–cell interactome (Porterﬁeld categorized as collective movements in which and Prescher 2015). clusters, sheets, or strands of cells move as a multicellular unit across or through tissue for Adherens junctions (AJs). AJs are protein developing and maintaining epithelial struc- complexes found at cell–cell junctions of epi- tures (Friedl and Gilmour 2009; Shamir and thelial and endothelial tissues that connect the Ewald 2015). More dynamic cell–cell junctions actin cytoskeleton of adjacent cells (Shapiro and lasting in the range of minutes are critical in Weis 2009). AJs depend on the homophilic mediating multicellular crowd behaviors in binding of calcium-dependent cadherins, which which groups of cells move individually, but interact via their intracellular domains with sev- coordinate their directionality and speed by eral regulatory and cytoskeletal proteins such as less stable and comparably short-lived adhe- p120-, a-, b-, g-catenin, and vinculin, among sions and cell–cell sensing (Theveneau and others (Harris and Tepass 2010). Although AJs Mayor 2013). Last, immune cells use even are usually associated with epithelial and endo- more short-lived cell–cell junctions for coordi- thelial tissues, it has been shown that mesenchy-

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Collective Cell Migration by Cell–Cell Junction Regulation

mal cells form transient adhesion complexes in plex (Baum and Georgiou 2011). Consequently, which type I N-cadherin, together with the full AJ are central hubs controlling cell–cell cohe- repertoire of intracellular adhesion proteins sion and collective cell migration underlying (p120, a-, b-, g-catenin, and vinculin), are en- tissue dynamics and remodeling. gaged (Theveneau and Mayor 2012a). Both E- and N-cadherin-based AJs control apicobasal, Tight junctions (TJs). TJs are adhesion com- as well as front–rear, polarity of interacting cells plexes in which the plasma membranes of adja- (Venhuizen and Zegers 2016). cent cells become closely associated, forming an The main functional difference between ep- impermeable barrier within the tissue. TJs are ithelial and mesenchymal AJs is their stability: indispensable for creating a barrier between dif- epithelial junctions tend to be more stable (in ferent regions of the body, and their main role is the range of hours to days), whereas mesenchy- to function as paracellular gates that restrict dif- mal junctions are transient (minutes to hours) fusion on the basis of size and charge. TJs are (Scarpa et al. 2015). The stability of AJs is con- composed of transmembrane proteins (claudin, trolled by several mechanisms, including endo- occludin, tricellulin, and marveld3) that seem cytosis and cytoskeletal regulation. Endocytosis sufﬁcient to trigger at least some of the aspects of AJ receptors and adapters occurs both by required in TJ formation, including mechanical clathrin-dependent and -independent mecha- junction stability and apicobasal polarity of nisms (Delva and Kowalczyk 2009; Schill connected cells (Zihni et al. 2016). Other TJ and Anderson 2009), which cooperate with reg- transmembrane adhesion proteins comprise ulation by Rho family GTPases. For example, the junctional adhesion molecules (JAMs), Cdc42 works upstream of Par6/aPKC and which enhance TJ stability and turnover (Ebnet Cdc42-interacting protein 4 (CIP4), which con- et al. 2004; Luissint et al. 2014). The intracellu- trol actin dynamics at the internalization site lar function of TJs depends on a dense network (Harris and Tepass 2010). Besides controlling of proteins, composed of ZO1, ZO2, ZO3, plus the stability of cell–cell interactions, Rho a large number of other adaptor proteins (Van GTPases, via PAK and bPIX, are reciprocally Itallie and Anderson 2014). By binding several controlled by AJs in which they play an essential transmembrane and adaptor proteins, TJs con- role on actin dynamics (Zegers et al. 2003; trol various signaling pathways involved in actin Zegers and Friedl 2014). Interaction between organization, cell polarity, as well as transcrip- cadherin–catenin clusters leads to the recruit- tional regulation (Gonzalez-Mariscal et al. ment of the Rac guanine nucleotide exchange 2014). The interaction of TJ proteins with the factor (GEF) TIAM1, which activates the Rho actin cytoskeleton seems to be essential for GTPase Rac1, and the activation of Rac1 in lead- junction formation and turnover. For example, er cells is, in turn, required for the formation of myosin light chain kinase stimulates TJ remod- cell protrusions and traction forces observed at eling and occludin internalization during the edge of a cell cluster during collective cell inﬂammation (Herrmann and Turner 2016). migration (Hordijk et al. 1997; Kovacs et al. Rho GTPase signaling is also controlled by TJ- 2002; Mertens et al. 2005). Another activator associated proteins: RhoA, Cdc42, and Rac are of Rho GTPases within the AJ is Nectin, and regulated by GEFs recruited to cingulin, ZO1, Nectin-like proteins, a family of Ig-like cell ad- and tricellulin (Otani et al. 2006; Terry et al. hesion molecules (CAMs) (Takaiet al. 2008). To 2011; Oda et al. 2014). Thereby, TJs form a cen- aid the formation of AJ, nectin recruits afadin tral hub between cell–cell interactions and actin and ponsin, which lead to the activation of dynamics (Balda and Matter 2016). Cdc42 and Rac and cytoskeletal remodeling at the site of cell–cell contact (Fukuyama et al. Gap junctions (GJs). GJs are intercellular 2006). The interaction between AJs and actin membrane channels made up of a multigene is mutual, leading to an increase in the stability family, called connexins in vertebrates (Willecke of cortical actin toward the maturing AJ com- et al. 2002). GJs are specialized junctions char-

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P. Friedl and R. Mayor

acterized by close apposition of the plasma adhesion molecule L-selectin is cleaved by shed- membranes between neighboring cells and con- dases of the metalloprotease and ADAM fami- tain a hydrophilic channel that mediates the lies, and is protected from this cleavage by in- intercellular passage of molecules .1 kDa in tracellular regulators, which engage with its size. The extracellular domains of connexins cytoplasmic domain, including calmodulin form a tight connection between adjacent cells and moesin (Kahn et al. 1998; Ivetic et al. contributing to cell-cell adhesion. Connexins 2002). IgCAMs have been reported to associate interact with several proteins to form multipro- with a range of other proteins at the cell mem- tein complexes, which are important in cell-cell brane, including growth-factor receptors, integ- junction stability and function. For example, rins, and cadherins, and with intracellular pro- Cx43 interacts with N-cadherin and other teins, such as effectors of signal transduction members of the AJ complex (Xu et al. 2001), pathways and cytoskeletal proteins (Juliano as well as cytoskeletal proteins such as microfil- 2002), and thus contribute to a range of signal- aments and microtubules (Wei et al. 2004). ing programs involved in cell adhesion and mi- Phosphorylation of the cytoplasmic domain gration. of connexin is critical in regulating GJ assembly, trafficking, channel gating, and turnover. GJs Slit/Robo. Slit/Robo corresponds to the contribute to cell migration during develop- Roundabout receptors (Robo) and their Slit li- ment and in homeostatic processes such as gand. Robo receptors belong to the superfamily wound healing (Kotini and Mayor 2015), and of IgCAMs and engage in both homophilic and it has been proposed that their channel activity heterophilic interactions (Hivert et al. 2002). could be important for cell coupling and coor- Slits are the principal ligands for the Robo re- dination during migration (Lorraine et al. ceptors (Kidd et al. 1999), which, together with 2015). heparan sulphates, form a ternary complex required for signaling (Ypsilanti et al. 2010). The IgCAMs. IgCAMs correspond to immuno- cytoplasmic domains of Robo do not possess globulin-like cell-adhesion molecules contain- catalytic activities and, therefore, interact with ing one or more Ig-like domains in their extra- different signaling molecules to exert their spe- cellular regions. IgCAMs are expressed in a wide cific effects; these include netrin and several variety of cell types, such as cells of the nervous GTPase activating proteins (GAPs) and GEFs system, leukocytes, and epithelial and endothe- that control actin cytoskeletal dynamics by reg- lial cells (Cavallaro and Christofori 2004). By ulating the activity of RhoA, Rac1, and Cdc42 homophilic and heterophilic interactions of (Ypsilanti et al. 2010). The activity of Slit/Robo, their Ig-like domains IgCAMs mediate adaptive including adhesion, is controlled by transcrip- cell–cell interactions and play an important role tional regulation and endocytosis and degrada- in cell migration (Cavallaro and Christofori tion (Keleman et al. 2005). Slit–Robo interac- 2004). IgCAM adhesion is regulated by lateral tion typically mediates cell repulsion, but in oligomerization, which in turn depends on some cases also supports cell–cell adhesion. phosphorylation of their Ankyrin-binding do- The formation of cranial ganglia requires the main (Garver et al. 1997). A second mechanism adhesion to different cell types, and increased that controls IgCAMs-mediated adhesion is adhesion between neural crest and placodes is based on their internalization or recycling promoted by an interaction between Robo2/ from the plasma membrane; for example, the Slit1, which increases the N-cadherin-depen- internalization of aplysia cell adhesion molecule dent adhesion between these cells (Shiau and (apCAM) is controlled by phosphorylation by Bronner-Fraser 2009). Slit/Robo interactions mitogen-associated protein (MAP) kinase (Bai- are also involved in collective cell migration ley et al. 1997). A third mechanism that regu- of neural crest cells during development and lates IgCAM-based cell adhesion is their proteo- endothelial cells in angiogenesis (Legg et al. lytic cleavage. For example, the leukocyte 2008).

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Collective Cell Migration by Cell–Cell Junction Regulation

Ephrin/Eph receptor. Ephrin/Eph receptor gagement results in the formation of focal ad- corresponds to a pair of ligands and receptors hesion complexes of varying sizes and func- involved in short-distance cell–cell signaling. tions, which interact with F-actin and recruit Eph are Tyr kinase receptors and ephrins are FAK and Src, leading to the activation of sig- membrane-tethered ligands, which can elicit naling pathways involving extracellular signal– signaling that affects the cytoskeleton, mediat- regulated kinase (ERK), c-Jun N-terminal ki- ing primarily cell repulsion but, depending on nase (JNK), and small GTPases (Bouvard et al. context, also cell–cell adhesion (Kania and 2013). Interaction of integrins with cadherins Klein 2016). Phosphorylation of the intracellu- and selectins has been proposed to be required lar domains of Ephs regulates the recruitment of for the participation of integrins in cell–cell effector proteins, such as the noncatalytic re- adhesion (Bouvard et al. 2013). gions of Tyr kinase adaptor protein 1 (Nck1) and Nck2, Vav2 and Vav3, Src, a2-chimerin, and ephexins, which directly regulate actin or CELL–CELL ADHESION STATES AND modulate the activity of the small GTPases DYNAMICS RhoA and Rac1 (Kania and Klein 2016). Nor- The type and durability of cell–cell adhesion mal morphogenesis of the neural tube and neu- and cytoskeletal interaction systems that are en- ral progenitors requires ephrin-dependent cell– gaged by stationary and moving cells provide a cell adhesion (Arvanitis et al. 2013), and alter- range of adhesion strategies between cells, native usage of different splice forms of Eph which jointly define the level of collective adhe- receptor was implicated in mediating cell–cell sion and polarity, junction dynamics, and the coupling during embryonic development. Eph type of collective migration. The spectrum of signaling promotes the formation of AJ through tissue fluidity can be found to vary, in a cell- interaction with E-cadherin and TJs via the in- and context-dependent manner, from fully teraction with claudin (Dravis and Henkemeyer immobilized, highly contractile to loosely con- 2011). Likely, the consequences of Ephrin/Eph nected but highly mobile collective cell–cell or- interactions for cell–cell contact stability de- ganizations and kinetics (Fig. 1). pend on the overall junction protein repertoire expressed by the cell. Ephrin/Eph has been Myoblast fusion and myofiber formation. shown to be important for collective movement; Myofibers are multicellular syncytia that de- for example, the formation of the thymus anlage velop by the fusion of individual myoblasts. requires EphB/ephrin B, which seems to sup- Rather than forming a collectively migrating port collective mobility by a collective separa- group, myoblasts remain stably anchored to tion mechanism (Foster et al. 2010). the substrate while establishing stable cell–cell junctions that enable contractility across many Integrins. Integrins are transmembrane cells but show little junction dynamics. Myo- proteins that connect the cytoskeleton with blast interactions engage multiple receptor the extracellular matrix (ECM). ECM ligands systems in parallel, including focalized high- for integrins include fibronectin, vitronectin, density accumulation of M- and N-cadherin, collagen, and laminin, among others, which, neural cell adhesion molecule (NCAM), vascu- beyond their well-established function as lar cell adhesion molecule (VCAM-1), meltrin, structural connective tissue scaffolds, also and integrins (Fig. 1A) (Charrasse et al. 2006; may be located between cells and contribute Abmayr and Pavlath 2012; Ozawa 2015). Once to cell–cell interactions (Barczyk et al. 2010). myoblasts connect with each other, individual Integrins interact with F-actin and intermedi- mobility is largely disabled, whereas collective ate filaments allowing a mechanical coupling contractility and force transmission across between the cytoskeleton and the ECM, and cell–cell junctions are gained, particularly act as important transducers of mechanical through the actomyosin cytoskeleton, which forces (Fagerholm et al. 2005). Integrin en- develops prominent stress fibers under the

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E-cadherin ieti ril as article this Cite IgCAMs, integrins Eph/ephrins Slit/Robo Tight junctions Occludins, claudins Gap junctions Molecular organization odSrn abPrpc Biol Perspect Harb Spring Cold

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Figure 1. Composition of cell–cell adhesions and related types of collective cell behaviors. Morphological organization of

2017;9:a029199 cell–cell interactions, related collective cell dynamics (upper panels), and their respective stability (cyan), molecular composition (blue), and multicellular function outcomes (pink; bottom panels). Different examples show variable levels of cell adhesion (blue dots) and cell movement (arrows, direction of migration). (A) Myoﬁber network. (B) Gut epithelium renewing. (C) Branching morphogenesis. (D) Drosophila border cells. (E) Neural crest. (F) Leukocytes. IgCAMs, immunoglobulin-like cell-adhesion molecules; Robo, roundabout receptors. Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press

Collective Cell Migration by Cell–Cell Junction Regulation

control of RhoA and bridges multiple cell bod- and turbulent movements remains to be clari- ies for coordinated rhythmic contractility of ﬁed (Nanba et al. 2015). By coupling apico- the multicellular ensemble (Charrasse et al. basal polarity with high junction stability, 2006). Thus, in fusing myoblasts high junction sheet migration along a two-dimensional stability mediated through overlapping adhe- (2D) substrate layer as guidance cue is a sion systems and cytoskeletal linkages support conserved and important type of collective mi- mechanically very stable junctions, which me- gration of a mature epithelium. Accelerated diate collective contractility and eventually cell variants of epithelial sheet migration are ob- fusion, but discourage position change of the served as sheet migration during the wound group as a whole and individual cells within closure of epithelial defects and epithelial mor- the group. phogenesis.

Epithelial sheet migration. Mature monolay- Sprouting strands. When invading 3D tis- ered epithelia display stable cell–cell in- sues, epithelial and endothelial cells typically teractions, established by E-cadherin- and move collectively to form linear, branched, b-catenin-based AJs, combined with apical or network-like strands (Fig. 1C). Collective desmosomal junctions and TJs; these jointly sprouting underlies the branching morphogen- mediate mechanically robust multicellular esis of epithelial tissue and organs with integrity, apicobasal polarity, and barrier branched or lobular structure, including the function (Wong et al. 1998; Takeichi 2014). trachea, kidney, thymus, and the mammary Whereas the epithelium as tissue remains an- gland (Gray et al. 2010). Sprouting hemo- or atomically stable to sustain live-long mechan- lymphangiogenesis occurs during revasculari- ical and functional integrity, epithelial renewal zation of tissue after injury (Senger and Davis in several tissues, including the intestine and 2011). As a biomechanical principle of sprout- the epidermis, depends on constitutive collec- ing in differentiated endothelia and epithelia, tive sheet migration coupled to cell prolifera- one or several leader cells form a leading tip or tion and sheet expansion (Wong et al. 1998; terminal end bud that protrudes forward, Nanba et al. 2015). The renewal of the gut whereas the rear cells undergo apicobasal polar- epithelium is initiated by releasing precursor ization to form avascular lumen or duct (Hueb- cells from the stem cell pool, which resides at ner et al. 2016). The cell–cell junctions of in- the bases of the crypts, and that then change vading epithelial strands are dependent on E- position and move upward along the basement cadherin-based AJs, desomosomal, and TJs membrane toward the tips of the villi (Ritsma (Shamir and Ewald 2015), whereas vascular et al. 2014). Because moving cells remain fully strands depend on VE-cadherin and TJs (Sen- coupled to their neighbors by lateral junctions ger and Davis 2011). Commonly, these cell and the intestinal basement membrane via strands preserve apicobasal polarity, form lumi- their basal plane, they move as cohesive sheets na, and deposit an abluminal basement mem- in the upward direction (Fig. 1B) and, addi- brane as they move, as has been observed during tionally, undergo a controlled number of cell vascular, mammary gland, kidney, and tracheal divisions (Wong et al. 1998; Nanba et al. 2015). development (Riggins et al. 2010; Nguyen- The mechanics of lateral sheet migration is Ngoc et al. 2012). When apicobasal polarity is not fully resolved. Likely, cryptic lamellipodia lacking, as in dedifferentiated tumor cells, col- generate traction force toward the substrate lective strand invasion occurs as solid ﬁnger-like along the sheet, whereas the apical cell–cell multicellular protrusions with no lumen junctions transmit collective actomyosin con- formed (Wolf et al. 2007; Nguyen-Ngoc et al. tractility to enable slow movement along the 2012). basement membrane (Farooqui and Fenteany 2005; Zegers and Friedl 2014; Bazellieres et al. Moving sheets and clusters. In morphogen- 2015), but the role of additional rotational esis and during cancer invasion, cell sheets and

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P. Friedl and R. Mayor

detached groups of variable size, which retain tissue (Ilina et al. 2011; Haeger et al. 2014). cohesive cell–cell junctions between cells, mi- Collectively, moving loose networks are medi- grate along 2D and three-dimensional (3D) tis- ated by complex morphological junctions me- sue scaffolds (Fig. 1D) (Friedl et al. 1995; Alex- diated by N-cadherin for cell–cell adhesion and ander et al. 2008; Montell et al. 2012). Epithelial additional receptors mediating repulsive sig- sheet movement is initiated by a row of leader nals, including Ephrin/Eph receptors (Theve- cells coupled to follower cells by AJs containing neau and Mayor 2011). As a consequence, cells E- or P-cadherin (Chapnick and Liu 2014; coordinate their polarity and respond to extra- Plutoni et al. 2016), and sheet displacement cellular signals as a group, but also retain the depends on coordinated traction force genera- remarkable ability of moving individually. Mes- tion between leader and follower cells, which are enchymal tumor cells develop ALCAM-positive distributed across cell–cell junctions by the cell–cell junctions when moving through con- actomyosin cytoskeleton (Brugues et al. 2014; fined space, and gain many properties of collec- Reffay et al. 2014; Bazellieres et al. 2015). Mov- tive invasion, including shared migration path, ing clusters can be epithelial, such as the lateral cell–cell junctions, and alignment of border cells moving along the boundaries of front–rear polarity and mitotic planes (Haeger large nurse cells of the developing Drosphila et al. 2014). But they also retain the ability to ovary, or mesenchymal, such as moving neo- rapidly detach in response to extracellular sig- plastic sheets in rhabodomyosarcoma explant nals such as growth factors, altered tissue geom- culture (Friedl et al. 1995). The activity of leader etry, or matrix metalloproteinase (MMP) avail- cells depends on extracellular stimuli, such as ability (Wolf et al. 2007; Ilina et al. 2011). ECM ligand or soluble factors (e.g., transform- Conceptually, collective networks retain prop- ing growth factor b, TGF-b), inducing MAP erties of both collective and individual cell kinase signaling and downstream Rac1 for pro- movements, as well as multicellular streaming, trusion formation and direction sensing (Khalil and further show a high level of stochasticity and Friedl 2010; Chapnick and Liu 2014). Lead- (“noise”) in switching between individual and er cell polarity is further supported by AJ sig- collective behaviors, which render experimental naling, which controls leader cell polarization classification sometimes challenging and re- and anterior protrusion dynamics (Khalil and quires quantitative analysis as well as mathe- Friedl 2010; Mayor and Etienne-Manneville matical modeling (Huang et al. 2015). As a de- 2016). In contrast to homeostatic sheet migra- fining characteristic for collective cooperativity, tion, which forms a continuum without leading the cells moving as a network can respond more and trailing edges, the mechanisms defining re- efficiently to external signals when they are part traction of the rear cells in moving clusters re- of groups rather than as individual cells (The- main unclear. veneau et al. 2010).

Moving cell networks. A more flexible type Leukocyte swarming and aggregation. When of collective migration, used by neural crest and activated, moving leukocytes show a strong ten- other mesenchymal cells, as they move in a co- dency to interact with each other, coordinate ordinated manner as loosely cohesive group in a their migration for “swarming” behaviors, and cell-type and context-dependent way, with a aggregate. In activated lymphoblasts, aLb2 in- variable tendency to individualize (Fig. 1E) tegrin/ICAM-1–dependent cell–cell junctions (Scarpa et al. 2015). Examples are the migration transiently interact and coordinate their migra- of neural crest cells in developing embryos, neu- tion as cell pairs or small clusters of variable ronal/astrocyte networks (Scarpa et al. 2015), stability (Gunzer et al. 2004; Malet-Engra et al. glioma cells retaining filamentous cell–cell in- 2015). As moving myeloid leukocytes converg- teractions while moving through complex brain ing toward damaged or infected tissue regions, parenchyma (Osswald et al. 2015), and mesen- chemoattractant guidance leads to highly coor- chymal tumor cells moving through confining dinated crowd behaviors with head-to-tail ori-

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Collective Cell Migration by Cell–Cell Junction Regulation

entation and frequent cell–cell interactions, A fundamental morphogenetic process that which can eventually transit to firm clustering allows tissues to develop and remodel and that that depends on b2 integrin availability (Waite depends on the regulation of cell–cell adhe- et al. 2011; Lammermann et al. 2013). Thus, sions is the epithelial-to-mesenchymal transi- at the low end of cell–cell adhesion, indivi- tion (EMT). In response to extracellular trig- dually moving leukocytes may coordinate gers, including cytokines, growth factors, and their amoeboid movements with neighboring metabolic stress, EMT induces the down-regu- cells by short-lived cell–cell junctions (seconds lation of E-cadherin but up-regulates N-cad- to minutes), and rapidly transit toward con- herin, which lowers cell–cell adhesion strength tact strengthening and aggregation into a and apical-basal cell polarity, and favors migra- multicellular cluster. Depending on experimen- tory and invasive properties (Thiery et al. 2009). tal context, such clusters may be immobile Traditionally, full EMT has been considered es- and transiently close an interstitial wound sential for the migration as it was thought that (Lammermann et al. 2013) or, under chemotac- only mesenchymal, but not epithelial cells, were tic and free-space conditions, even show collec- able to migrate. However, recent work indicates tive coordination and migration (Malet-Engra that EMTshould be considered as a spectrum of et al. 2015). intermediary phases, ranging from full EMT to In summary, for very different cell types partial, or even quite subtle states of EMT with and biological contexts, the organization and very variable effects on cell mobility and migra- stability of cell–cell junctions, together with en- tion type (Fig. 2) (Nieto et al. 2016). Well-stud- vironmental parameters, determines the mor- ied examples of collective cell migration during phological and functional types of collective development, which are initiated by or maintain movement. Consequently, alteration of adhesome degree of EMT, include the migration of sion and environmental parameters may im- border cells in Drosophila, the lateral line pri- pose an adaptation response and significant mordium in zebrafish, and the neural crest in plasticity of collective behaviors. amphibian and zebrafish (Mayor and Etienne- Manneville 2016). The precursors of all these tissues are epithelial cells that undergo an TUNING COLLECTIVE MIGRATION: EMT to initiate their migration; the degree VARIABILITY AND TRANSITIONS and pattern of collective cooperation during The molecular variability of cell–cell junctions migration thereafter reflects varying cell–cell and their different linkages to the cytoskeleton junction organization and dynamics main- not only explain distinct types of collective tained by varying coexistence of epithelial and movements; when regulated within the same mesenchymal programs (Fig. 2). The zebrafish cell type, by extracellular chemical or physical lateral line primordium represents collective cell signals, collective migration may be induced or migration, which retains both epithelial and modulated, with consequences for group be- mesenchymal characteristics as a default state havior and tissue integrity and function. (Fig. 2A,B) (Ghysen and Dambly-Chaudiere 2004). Cells of the primordium express E-cadherin and show foci of the TJ protein ZO1 and Tissue Morphogenesis and Regeneration aPKC at the center of the tightly packaged pri- Morphogenesis involves the complex and coor- mordium (Revenu et al. 2014), similar to ma- dinated rearrangement of tissues and massive ture epithelium. On the other hand, cells par- movement of cells. In particular, the initial for- ticularly located at the edge of this cell group mation of the body shape, the early separation display typical mesenchymal characteristics, of the principal tissue types, and the organiza- such as reduced apicobasal polarity and the tion of specific organs depend on different types presence of highly dynamic actin-rich lamelli- of collective cell migration. Similar morphoge- podia-like protrusions at the basal interactions netic processes are implicated in regeneration. to the tissue (Lecaudey et al. 2008; Hava et al.

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P. Friedl and R. Mayor

ADStable epithelium Collective network migration

Full EMT Partial EMT

Moving epithelium B Stochastic? sheet Promigratory stimulus? Altered tissue geometry? Leader cell E Individualization

C Collective detachment cluster

Leader cell

Epithelial Mesenchymal E-cadherin Other junctions (N-cadherin, IgCAMs, etc.)

Figure 2. EMT spectrum tuning the modes of collective and individual-cell migration. (A) Resting epithelial tissue. (B) Partial EMT in the leading cells can retain cell–cell junctions and promote epithelial sheet migration. (C) Cluster migration after group detachment from the main tissue. Migrating clusters can maintain apicobasal polarity, strong and stable cell adhesion mediated mainly by E-cadherin, or undergo further mesenchymal plasticity. (D, E) Full EMT leads to reduced cell adhesion, associated with down-modulated E-cadherin and increased N-cadherin expression, followed by loss of apicobasal polarity, acquisition of front–back polarity and increased individual motility. Transient junctions allow for collective network migration (D), and complete resolution of cell–cell junctions favors individualization and single-cell migration (E). EMT, epithelial-to- mesenchymal transition; IgCAMs, immunoglobulin-like cell-adhesion molecules.

2009). Thus, within the same moving cell tegrity of these tissues, with E-cadherin deﬁ- group, different interaction types are found, cient cells being excluded (Shamir and Ewald with strong cell–cell adhesions at the center of 2015). The leading front of the tube, which the migrating cluster and more mesenchymal drives collective mobility, undergoes a loosen- cells with weaker adhesions but higher actin- ing (but not ablation) of cell junction stability, mediated mobility at the periphery and in lead- for example, by maintaining a partial EMT er cells. in which E-cadherin-based junctions gain Branching morphogenesis in the lactating ﬂexibility and increase their turnover; concur- mammary gland and cell movements during rently cells in the rear position, which form gut homeostasis are also seemingly equivalent the extending tube, retain stable cell–cell junc- to the initial branching morphogenesis ob- tions and apicobasal polarity, and gradually served during development, as both processes downscale their migration ability (Shamir and require E-cadherin-mediated cell–cell cohesion Ewald 2015). Likely, similar reprogramming of for collective sprouting and tubule elongation; leader cells toward loosened junction organiza- depletion of E-cadherin interferes with the in- tion is active during neoplastic invasion of

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Collective Cell Migration by Cell–Cell Junction Regulation

breast cancer cells (Cheung et al. 2013; Cheung it confers sufficient fluidity on the cell cluster and Ewald 2014). Thus, tuning cell–cell junc- for it to migrate under physical constrains (Kur- tion stability regulates the degree of collective iyama et al. 2014). This increase in tissue fluid- dynamics. ity allows a dynamic exchange of neighbors As an example of a very transient EMT while retaining cell–cell interaction. followed by epithelial collective migration, Dro- In conclusion, collective cell migration dur- sophila border cells initiate their delamination ing morphogenesis involves a wide spectrum of from the epithelium by down-regulation of DE- cell adhesion strength, with highly cohesive cell cadherin for a short time period (few hours) sheets and clusters at one end and relatively (Fig. 2C) (Montell et al. 2012). A network of loose groups of cells at the other end. By spa- transcription factors, including Jing, SIX4, tially and temporally tuning cell–cell junction Yan, Similar (also known as HIF1a), Hindsight stability, a range of collective migration modes (HNT), and Jun-related antigen, is activated and patterns with different levels of cell–cell and controls the levels of DE-cadherin during cohesiveness is achieved to build tissue. border cell delamination and migration (Mon- tell et al. 2012). Levels of DE-cadherin need to Cancer Invasion and Metastasis be precisely regulated and deviations impair border cell migration; consequently, after ini- Collective invasion is an important strategy for tially reducing DE-cadherin levels during de- local tissue infiltration, as well as metastatic eva- lamination, moving border cell clusters still sion in epithelial tumors such as breast cancer, maintain substantial levels of both DE-cadherin squamous cell carcinoma, colon cancer, and and its binding partner armadillo (b-catenin) others, as well as in mesenchymal tumors (Ilina between neighboring border cells to maintain and Friedl 2009; Cheung and Ewald 2016). Sim- collective migration as a cluster (Peifer 1993; ilar to morphogenesis, the phenotypic and Niewiadomska et al. 1999; Sarpal et al. 2012). junctional organization of moving cancer cell As an example for even stronger mesenchy- groups varies greatly (“collective plasticity”). mal properties with few epithelial features re- In experimental live-cell models, all types of tained, in many species the neural crest under- collective movements can be adopted by tumor goes EMT to initiate migration (Thiery et al. cells including (1) cohesive sheets or strands, 2009; Theveneau and Mayor 2012b). In addi- typically detected in epithelial cancers; (2) iso- tion, after delamination a collective network- lated clusters detached from the primary/met- type migration is retained whereby loosely con- astatic lesion such as epithelial tumors and nected individually moving cells and more melanoma; (3) neuronal-like networks of con- tightly connected clustered cells both depend nected cells, detected in neuroectodermal tu- on cell–cell interactions for their migration mors, such as glioblastoma; or (4) as “jammed” (Fig. 2D) (Teddy and Kulesa 2004; Carmona- collective cohorts induced by spatially narrow Fontaine et al. 2008). A complex genetic net- tissue boundaries (confinement) of otherwise work is activated in the neural crest that leads transiently/loosely connected (single) cells in to and maintains EMT. A BMP4-Wnt1 signal- experimental melanoma and sarcoma models ing pathway activates a set of transcription fac- (Friedl et al. 1995, 2012; Nguyen-Ngoc and tors, including Snail1/2, Sox5/9/10, Foxd3 and Ewald 2013). Similarly, histological examina- Ets1, that modify the expression of cell–cell and tion of both patient lesions and mouse models cell–matrix adhesion molecules (Sauka-Speng- in vivo shows that the collective invasion pat- ler and Bronner-Fraser 2008; Theveneau and terns develop striking morphological and mo- Mayor 2012c). Thus, although neural crest lecular variability, depending on tumor type shows all the hallmarks of mesenchymal cells, and the tissue that is invaded (Weigelin et al. they obviously form transient AJs (Scarpa et al. 2012; Bronsert et al. 2014). 2015). The endocytosis of N-cadherin at the AJs Consistent with cellular diversity of collec- is essential for neural crest migration in vivo, as tive invasion programs, a range of cell–cell

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P. Friedl and R. Mayor

adhesion mechanisms supports collective inva- integrin signaling; and can redirect Rho-medi- sion of cancer cells. Epithelial tumors invade ated actomyosin contractility from cell–cell collectively, with duct-like patterns and E-cad- junctions toward cell–matrix interactions (Kal- herin and b-catenin positive cell–cell junctions, luri and Weinberg 2009; Parvani et al. 2013; with or without lumen formation, and with or Truong et al. 2014). These molecular repro- without up-regulation of EMTmarkers, includ- gramming events result in deregulated cell– ing Twist and Zeb1 (Cheung et al. 2013; Bron- cell contacts, loss of apicobasal polarity, includ- sert et al. 2014). Furthermore, both E- and ing degeneration of the lumen of otherwise N-cadherin can orchestrate AJs and cell–cell ductal and glandular structures, gain of front– interactions in cancer cells (Bronsert et al. rear polarity, and ultimately favor the gradual 2014; Zucchini et al. 2014). Besides cadherins, transition from epithelial to mesenchymal mi- Ig superfamily members and ephrins/EpH re- gration modes (Bryant et al. 2014). ceptor systems were implicated in mediating In addition to tumor cell individualization more labile or transient cell–cell interactions caused by full EMT, which allows for single-cell in cancer cells (Cavallaro and Christofori dissemination and metastasis, recent cell-based 2004; Haeger et al. 2014; Krusche et al. 2016). and modeling work indicates that EMT also As well, connexins may enable communication contributes to collective invasion with a high through GJs between connected tumor cells and likelihood of mixed behaviors after EMT, in- their inhibition reduces collective migration in cluding intermediate (e.g., metastable or hy- prostate cancer cells (Zhang et al. 2015). Similar brid) phenotypes such as detached collective to morphogenetic and homeostatic migration, or loosely connected migrating groups (Jolly collectives of migrating cancer cells display lead- et al. 2015). With such EMT-associated repro- er cells that engage with surrounding tissue gramming, or partial EMT, moving tumor cell structures via Rac-driven filopodal protrusions clusters may still maintain cell–cell contacts and integrin-mediated substrate adhesion (He- but simultaneously undergo a differentiation gerfeldt et al. 2002; Yamaguchi et al. 2015). switch toward embryonic features (Jolly et al. Collectively moving cancer cells retain a range 2015; Nieto et al. 2016). Thus, similar to mor- of actin dynamics, substrate adhesions, and phogenesis, the adaptability of collective inva- ECM remodeling functions, which typically sion programs allows a range of coping strate- are shared and coordinated between neighbor- gies for cancer invasion and metastasis in ing cells, generate tissue alignment and remod- different tissue environments (discussed in Te eling as an integrated process; these combined Boekhorst and Friedl 2016). parameters can further define the degree of cell– cell cohesion and individualization as an inte- CONCLUDING REMARKS grated function of cell–cell junction stability, MMPactivityand tissue organization, and space Cell–cell junctions emerge as central regulators (Scott et al. 2010; Friedl et al. 2012; TeBoekhorst of the type, efficiency, and fate of collective cell et al. 2016). movements. Here, we have proposed an integra- In recapitulation of morphogenesis pro- tive view to frame collective cell functions that is grams, EMTsignaling enhances cancer invasion distinguished by modular and often gradual and metastatic progression of epithelial cancers cell–cell adhesion regulation. We hope that by reprogramming cell–cell junctions (Kalluri this perspective may facilitate the understanding and Weinberg 2009). EMTweakens or fully dis- of multicellular dynamics with mixed pheno- solves cell–cell junctions between cancer cells, types, which are frequently observed in wet-lab- including AJs, desmosomes, and TJs. EMT also oratory experiments and also in mathematical up-regulates the expression of stromal proteas- modeling (Jolly et al. 2015; Te Boekhorst et al. es, which cleave cadherins; deregulates integrin 2016). By modulating the composition of cell– adhesion systems, for example, by switching b1 cell adhesions, collective movements are adap- to b3 integrin expression and enhancing aV tive in time and space in response to soluble and

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Collective Cell Migration by Cell–Cell Junction Regulation

structural tissue-derived signals, as well as geo- part of, for example, a cell-jamming transition metric tissue properties (Haeger et al. 2015; Te when cells are confined in tissue space, and Boekhorst et al. 2016). Thus, similar to single- thereby adopt emergent behaviors, including cell migration modes, which can switch between persistent intercellular adhesion and signal in- different types of mesenchymal and amoeboid tegration (Haeger et al. 2014; Sarkar et al. movements, collective migration modes can in- 2016). Thus, different junction states and envi- terconvert and adapt to local and global signals. ronmental conditions enable unique sets of Based on their range of stability, cell–cell emergent mechanical and signal integration junctions may be classified as (1) stable, cohe- beyond single cell behavior. Future classifica- sive with disabled cell position change, (2) sta- tion of different types of collective versus sin- ble, but dynamic, allowing cells to move relative gle-cell behaviors will depend on careful dis- to neighbors without resolving the junction, (3) section of each functional module associated partially stable, allowing transient detachment in a junction-, cell-type-, and tissue-specific and reintegration, and (4) short lived and par- context. tially repulsive. Emergent collective behaviors, Conceptual frameworks based on classify- that is, the ability of a cell group to perform ing types of collective movements and their tasks beyond the abilities of a single cell, are links to single-cell migration and other types reached as long as cell–cell junctions suffice to of tissue dynamics, such as tissue folding and coordinate behavior across scale. Examples are convergent extension, will further allow us to collective chemotaxis and durotaxis, which al- integrate molecular signaling concepts, for ex- low cell groups to respond to more shallow ample, on EMT or stemness, with varying de- chemical or physical gradients for directional grees of cell–cell cooperation. Based on their migration (Malet-Engra et al. 2015; Sunyer central function in defining the shape, molecu- et al. 2016). The gradual range of kinetic states lar composition, and duration of cell–cell co- complicates simple classifications as “collec- operation, multiscale analysis integrating si- tive” movement versus multicellular streaming multaneously engaged junction mechanisms versus predominantly single-cell dynamics. and their signaling cross talk will be required Typical collective cell migration is considered to delineate which individual and cooperative when stable cell–cell junctions support supra- functions guide or compromise collective deci- cellular coordination of cytoskeletal activity sion-making and outcome. across multiple cell bodies and even passive cell transport as part of group behaviors (Friedl et al. 2012). Likewise, emergent collective be- ACKNOWLEDGMENTS haviors can also be observed when cell–cell We thank Adam Shellard and Andra´s Szabo for junctions are transient junctions, particularly comments on the manuscript. Work from the in chemotactic gradient sensing and signal in- P.F. laboratory is supported by grants from the tegration. Thus, multicellular streaming behav- European Research Council (617430-DEEPIN- ior depends on the active movement of every SIGHT), NWO-Vici (918.11.626), Horizon cell but still retains multiple reciprocal cell– 2020 consortium MULTIMOT (634107-2), the cell interactions, which are limited in duration Cancer Genomics Center, and the MD Ander- and stability but enable collective gradient sens- son Cancer Center Moon Shot program, and ing (Theveneau et al. 2010; Ellison et al. 2016). from R.M. by grants from MRC and BBSRC. Last, individually moving cells may still engage with other cells in short-lived junctions, which may or may not induce repulsion and direc- REFERENCES tional change, and thereby retain cooperative Abmayr SM, Pavlath GK. 2012. Myoblast fusion: Lessons input from neighboring cells (Ellison et al. from flies and mice. Development 139: 641–656. 2016). As a special case, an otherwise loosely Alexander S, Koehl GE, Hirschberg M, Geissler EK, Friedl P. connected cell may upscale cooperativity as 2008. Dynamic imaging of cancer growth and invasion: A

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Tuning Collective Cell Migration by Cell−Cell Junction Regulation

Peter Friedl and Roberto Mayor

Cold Spring Harb Perspect Biol 2017; doi: 10.1101/cshperspect.a029199 originally published online January 17, 2017

Subject Collection Cell-Cell Junctions

Vascular Endothelial (VE)-Cadherin, Endothelial Signaling by Small GTPases at Cell−Cell Adherens Junctions, and Vascular Disease Junctions: Protein Interactions Building Control Maria Grazia Lampugnani, Elisabetta Dejana and and Networks Costanza Giampietro Vania Braga Adherens Junctions and Desmosomes Making Connections: Guidance Cues and Coordinate Mechanics and Signaling to Receptors at Nonneural Cell−Cell Junctions Orchestrate Tissue Morphogenesis and Function: Ian V. Beamish, Lindsay Hinck and Timothy E. An Evolutionary Perspective Kennedy Matthias Rübsam, Joshua A. Broussard, Sara A. Wickström, et al. Cell−Cell Contact and Receptor Tyrosine Kinase The Cadherin Superfamily in Neural Circuit Signaling Assembly Christine Chiasson-MacKenzie and Andrea I. James D. Jontes McClatchey Hold Me, but Not Too Tight−−Endothelial Cell−Cell Mechanosensing and Mechanotransduction at Junctions in Angiogenesis Cell−Cell Junctions Anna Szymborska and Holger Gerhardt Alpha S. Yap, Kinga Duszyc and Virgile Viasnoff Connexins and Disease Beyond Cell−Cell Adhesion: Sensational Mario Delmar, Dale W. Laird, Christian C. Naus, et Cadherins for Hearing and Balance al. Avinash Jaiganesh, Yoshie Narui, Raul Araya-Secchi, et al. Cell Junctions in Hippo Signaling Cell−Cell Junctions Organize Structural and Ruchan Karaman and Georg Halder Signaling Networks Miguel A. Garcia, W. James Nelson and Natalie Chavez Loss of E-Cadherin-Dependent Cell−Cell Adhesion Cell Biology of Tight Junction Barrier Regulation and the Development and Progression of Cancer and Mucosal Disease Heather C. Bruner and Patrick W.B. Derksen Aaron Buckley and Jerrold R. Turner

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Desmosomes and Intermediate Filaments: Their Integration of Cadherin Adhesion and Consequences for Tissue Mechanics Cytoskeleton at Adherens Junctions Mechthild Hatzfeld, René Keil and Thomas M. René Marc Mège and Noboru Ishiyama Magin

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