Collective migration modes in development, tissue repair and cancer

Abstract

Migrating cells have key functions in shaping tissues during development, repairing tissues after development and supporting cancer invasion and metastasis. In all these contexts, cells often maintain contact with their neighbours and move as a group, in a process termed collective migration. In this Review, we describe the elegant mechanisms used by collectively migrating cells in vivo to coordinate their movements and obtain directional information. We start by highlighting the diverse physiological roles that migrating collectives have within the body and then focus on dominant paradigms for the organization of migrating collectives including the roles of leader and follower cells, local cell-cell adhesion and signalling, and external guidance cues. By comparing collective migrations occurring during development and cancer, we bring into focus shared principles for collective cell movement and distinct strategies used by cancer cells for their own dispersal. Throughout, we pay particular attention to how migrating collectives display emergent properties not exhibited by individually migrating cells and how these properties provide the robustness needed for efficient cell movement.

Figure 1 -. Collective migration during development.

(a-d) Illustrations depicting five developmental models of collective migration highlighted in this review. For each panel, the organismal context for the migration is on the left, and the cellular arrangement of the migrating cohort and key cues that organize its movement are on the right. Magenta arrows indicate migration direction. (a) Border cells and follicular epithelial cells (follicle cells) are two cell types within Drosophila egg chambers (ovarian follicles) that migrate at different developmental stages. The border cells delaminate from the follicular epithelium and migrate though the nurse cells to the oocyte where they help to build the sperm entry channel in the eggshell. By contrast, the follicle cells undergo a rotational collective migration along their surrounding basement membrane that helps to create the elongated shape of the egg. (b) The neural crest is a vertebrate stem cell population that arises at the dorsal side of the neural tube and migrates ventrally through the body to produce many cell types. The cranial neural crest population of Xenopus shows particularly high collectivity in its movement. (c) The pronephric tubule cells of the zebrafish kidney migrate toward a centrally located glomerulus. This causes the tubules to bend outward from their glomerular attachment point and to lengthen. (d) The posterior lateral line of zebrafish is an array of sensory organs (neuromasts) that detects water movement. This array is built by a cellular primordium that deposits the neuromasts at regular intervals as it migrates toward the tail.

Figure 2 –. Collective migration during tissue repair

(a-b) Illustrations depicting two collective migrations that occur during tissue repair. For each panel, the organismal context for the migration is on the left, and the cellular arrangement of the migrating cohort is on the right. Magenta arrows indicate migration direction. (a) Collective migration is a key mechanism contributing to wound closure in many tissues. The illustration shows this phenomenon in the context of mammalian skin. (b) In the epithelial lining of the vertebrate intestine, cells are continually born at the bottom of invaginated crypts and shed from the top of evaginated villi. Recent work in mouse showed that movement between these points is driven both by pressure from cells division and active crawling along the epithelial basement membrane using cryptic protrusions (inset).

Figure 3 –. Collective migration during cancer metastasis

(a) Collective cancer invasion takes many forms in vivo. Clinically, tumors are typically formalin-fixed and embedded in paraffin blocks that are then reviewed by pathologist as thin 2D sections. With emergence of 3D optical clearing and automated reconstruction methods, the invasion front is shown to be predominantly collective in organization^–. Geometrically, tumors can form a variety of multicellular structures including sheets, strands, and chains dependent, in part, on constraints imposed by the local microenvironment. In addition, cancers can take unusual forms, such as buds (colon carcinoma), and invade into lymphatic and vascular circulation as large multicellular emboli (inflammatory breast carcinoma). In many transplantable cancer models, invasion patterns are more often a continuum of collective and single cell modes. (b) Timing of collective cell dynamics. Unlike developmental migrations that occur over hours to days, metastasis occurs over years and sometimes decades. These snapshots reveal tumor cell clusters across the continuum of the metastatic process, and present in key phases including within blood vessels and lymphatics and in circulation. Paired with genomic studies demonstrating polyclonality, these observations suggest that tumor cell clusters participate in metastatic dissemination to some organ sites. As patients develop fulminant metastatic disease, circulating tumor cell (CTC) clusters are detected in high abundance in peripheral blood, accompanied frequently by inflammatory and thrombotic complications. (c) Penetration of local and systemic barriers to metastasis. Migrating tumor cells must overcome multiple barriers to establish distant metastases. Collective migration enables multicellular polarization of cell states, migratory and proteolytic machinery, and spatially restricted metabolism, often in association with heterotypic interactions between cancer and non-cancerous cells of the tumor microenvironment (TME). The cohort is then able to invade toward vessels, via chemotactic or other guidance cues, and enter circulation by direct invasion, intercalation or vascular mimicry. Disseminating tumor cell clusters, which overlap in their properties with stem cells and metastasis-initiating cells, have minutes to hours to survive hematogenous circulation; for this reason, the circulatory phase is both instrumental yet challenging conceptually to disrupt therapeutically. (d) Migratory coordination between tumor cells is enforced by multiple mechanisms operating at specific cell membrane interfaces including juxtacrine receptor-ligand, adherens-junction based mechanotransduction, intercellular ligand accumulation, and zones of localized matrix and gradient remodeling. Additional interface mechanisms between tumor cells and noncancerous cells include tunneling nanotubes and exosomal intercellular transfer.

Figure 4. Collective migration enables robust cell dynamics

(a-d) Collective migrations induce emergent properties promoting tissue robustness. These properties include multitasking, redundancy, environmental transformation, and stability despite fluctuating environmental conditions. In turn, these properties enable rapid execution and adaption to complex, dynamic microenvironmental conditions occurring in development, tissue repair, and cancer metastasis.