TICB-812; No. of Pages 9 Review Plithotaxis and emergent dynamics in collective cellular migration 1,2 3 Xavier Trepat and Jeffrey J. Fredberg 1 Institute for Bioengineering of Catalonia, Ciber Enfermedades Respiratorias, and University of Barcelona, Spain 2 Institucio´ Catalana de Recerca i Estudis Avanc¸ats, Spain 3 Program in Molecular and Integrative Physiological Sciences, Harvard School of Public Health, 02115 Boston, MA For a monolayer sheet to migrate cohesively, it has long tissue, a tip cell guides collective migration of sprouting been suspected that each constituent cell must exert capillaries into the wounded region. physical forces not only upon its extracellular matrix Collective cellular migration plays a role not only in but also upon neighboring cells. The first comprehensive development, physiology, and repair, but also in devastat- maps of these distinct force components reveal an unex- ing diseases including cancer. In the vasculature and pected physical picture. Rather than showing smooth and lymphatics of cancer patients, increasing evidence now systematic variation within the monolayer, the distribu- points to the existence of clusters of metastatic cells that tion of physical forces is dominated by heterogeneity, invade collectively [7,8]. Collective invasion processes are both in space and in time, which emerges spontaneously, also evidenced in histopathological sections of a broad propagates over great distances, and cooperates over the diversity of differentiated carcinomas in which the primary span of many cell bodies. To explain the severe rugged- tumor is surrounded by secondary cancer cells that take ness of this force landscape and its role in collective cell the form of clusters, chains, and sheets [9]. guidance, the well known mechanisms of chemotaxis, durotaxis, haptotaxis are clearly insufficient. In a broad If complexity is an essential feature, how much is range of epithelial and endothelial cell sheets, collective enough? cell migration is governed instead by a newly discovered Because of its importance to so many branches of biology, emergent mechanism of innately collective cell guidance the question of collective cellular migration has been – plithotaxis. studied for a long time, at multiple levels, and in many different experimental model systems. For the particular Cellular motility within complex multicellular systems questions at issue in this review, the intercellular forces In essential physiological functions including morphogen- that arise when only two or three cells interact in vitro esis, wound healing, and tissue regeneration, the prevalent [10–12] are of substantial interest even though such mode of cellular migration is collective. Collective cellular systems are not sufficiently complex to demonstrate migration is also recognized as being a ubiquitous mecha- the emergent phenomena described below. Of greater nism of invasion in cancers of epithelial origin. Indeed, interest, in principle, would be the distribution of inter- virtually all living tissue is constructed and remodeled by cellular forces in migrating cell sheets or clusters in vivo, collective cellular migration [1]. During morphogenesis, for but these distributions are not yet measurable. Accord- example, the complex architecture of branched organs such ingly, we focus here on the intermediate situation of the as lung, kidney, pancreas, and vasculature is shaped by extended epithelial or endothelial cell sheet in vitro. Such collective migration of sprouting vessels and ducts [2,3]. In systems are sufficiently simple that one can measure the other developmental processes, clusters of cells are first distribution of physical forces that guides collective cel- specified at one location but then travel long distances to lular migration, as described below, but are sufficiently the location where they carry out their ultimate biological complex to reveal new phenomena and physiological function. In the case of oogenesis in Drosophila, for exam- mechanisms. ple, the border cell cluster squeezes though nurse cells to migrate cohesively from follicle to oocyte [4]. Similarly, the Glossary lateral line sensory machinery of the zebrafish is deposited Stress: force per unit area. by a primordium comprising roughly 100 cells that travels Normal stress: local stress exerted normal to a defined surface. the entire anterior-posterior axis of the embryo [5]. Shear stress: local stress exerted tangent to a defined surface. Traction force: the local stress exerted by a cell upon its substrate. Some of these morphogenetic mechanisms are recapitu- Principal stresses: in any continuum, the local stress field can be decomposed lated in postnatal life to repair injured tissue [6]. Re- into a maximal and minimal principal stress, each acting along a correspond- epithelialization during wound healing, for example, ing principal orientation. Principal orientations: orientations that are mutually perpendicular and define involves the collective migration of epithelial cells and the directions along which the shear stress is zero. fibroblasts onto and through a denuded basement mem- Plithotaxis: the tendency for each individual cell within a monolayer to migrate brane. To provide oxygen and nutrients to newly assembled along the local orientation of the maximal normal stress, or equivalently, minimal shear stress. Plithotaxis requires force transmission across many cell– cell junctions and therefore is an emergent property of the cell group. Corresponding author: Fredberg, J.J. ([email protected]). 0962-8924/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2011.06.006 Trends in Cell Biology xx (2011) 1–9 1 TICB-812; No. of Pages 9 Review Trends in Cell Biology xxx xxxx, Vol. xxx, No. x In connection with such model systems in vitro, the This observation suggests that global motion of the group traditional scratch wound-healing assay initiates collec- could be a simple consequence of the self-propelled motion tive cellular migration by the sudden creation of free space, of each of its individual constituent cells, much as each together with the creation of injured cells near the denuded automobile advances in traffic, as each fish swims in a boundary, and, in most cases, the simultaneous creation of school, or as each bird flies in a flock. In such mathematical a spatial gradient in the composition of the extracellular models, each actor undergoes independent random motion, matrix, ECM [13,14]. It is perhaps not surprising that or independent random motion with directed drift in a injury to boundary cells and gradients in ECM composition manner analogous to directed diffusion. As in automobile have profound effects upon the monolayer migration, but traffic, fish schools and bird flocks, a physical picture of newer methods have shown that free space – without collective cellular migration based upon independent creation of cellular injury or gradients in ECM composition actors that are each self-propelled implies that the average – is sufficient to initiate collective cellular migration mechanical stress transmitted from cell-to-cell within the [15–19]. Although cell injury and/or gradients of ECM sheet must be zero. composition lead to different initial conditions, boundary Still a different physical picture is that the leading edge conditions, and, potentially, different mechanisms of cellu- is not at all dragging follower cells along, but rather is lar migration, the simpler situation in which collective being pushed forward by the pressure created by cell migration is not complicated by these factors comprise proliferation in the ranks far behind. This mechanism the focus of this review. has long been assumed to be the mode of expansion for proliferative tissues such as epidermal sheets or tumors The hidden hand [28]. Such a pressure is a compressive stress – similar in Collective cellular migration in a wide range of circum- kind to, but opposite in sign from, mechanical tension [29]. stances tends to be regulated by the same extrinsic cues Each of these three alternative physical pictures is that guide single cells in isolation, but these cues ordinarily invoked widely in the literature, and corresponds to one act on but a small subset of cells that in turn guide naı¨ve of three competing schools of thought. But no matter how followers [1,20]. How does this subset within the motile plausible each might seem, or how strong the structural or group guide its global motion? The notion of a relay of biochemical evidence might be, these alternatives are mu- guidance molecules is well studied, and it has it been tually exclusive. At any given position at any given time, the suggested that the direct transmission of physical forces mechanical stress at the cell-cell junction can be positive from cell–to–cell can be transduced locally and then used as (tensile) or negative (compressive) or zero, but logically a signaling cue to guide local motion [21]. In addition, these cannot be all three at once. Yet another distinct possibility same physical forces might act to steer mechanically local is that the cell–cell junction might also support mechanical cellular motions [21]. Whereas it seems certain that group shear stress (Box 1); compression and tension are stresses migration is regulated in some fashion by the combined exerted normal to the junctional surface (although with influences of extrinsic cues, cell–cell signaling, and local opposite signs) whereas shear stress is exerted tangent to mechanical cell–cell