Collective cell migration is a fundamental biological process where groups of cells move together in a coordinated manner across tissues. This contrasts with individual cell migration, where cells move solitarily without maintaining strong connections to their neighbors. Collective cell migration involves a cohesive group of cells, such as a sheet, strand, tube, or cluster. This synchronized movement is a widespread phenomenon throughout living organisms, playing a role in various physiological and pathological processes.
The Mechanics of Group Movement
Cells achieve collective movement through a complex interplay of physical connections and internal forces. A primary mechanism involves cell-cell adhesion, where cells remain linked to one another as they move. Proteins called cadherins, such as E-cadherin and N-cadherin, are key components of these adherens junctions, forming strong, calcium-dependent connections between cells. These cadherin-based junctions not only maintain tissue integrity but also connect to the internal actin cytoskeleton via proteins like beta-catenin and alpha-catenin, allowing for the transmission of mechanical forces across the cell group.
Within these moving groups, a “leader-follower” dynamic emerges, guiding the collective’s direction. Specialized leader cells form at the front, extending protrusions and sensing cues from the environment. These leader cells pull the trailing follower cells, which make up the majority of the collective and maintain the group’s cohesion through intercellular contacts. While leader cells exert significant traction forces, follower cells also contribute to force generation and help organize the collective movement.
The generation of mechanical forces is powered by the cell’s internal machinery, particularly the actin cytoskeleton and myosin motor proteins. Actin filaments rapidly polymerize at the leading edge of cells, pushing the membrane forward to create new protrusions like lamellipodia. Myosin II motors then interact with these actin filaments, generating contractile forces that pull the cell body forward and are transmitted through adhesion sites to the extracellular environment. This actomyosin contractility, along with the activity of small GTPases like RhoA, is key to shaping cell movement and transmitting tension throughout the migrating group.
Cells within the collective also communicate to coordinate their actions. This coordination occurs through both direct physical contact and chemical signaling. For instance, cells can secrete chemical attractants, leading to “co-attraction” that helps maintain cell density and guide movement. Contact inhibition of locomotion (CIL) is another mechanism, where cells change their direction of movement after colliding with another cell. These communication networks ensure that the group moves as a synchronized unit.
Building and Repairing Tissues
Collective cell migration is a process during embryonic development, shaping the structure of an organism. During gastrulation, the early embryo undergoes rearrangements where sheets of cells migrate and deform to establish the basic body plan and germ layers. For example, the prechordal plate, a group of mesendoderm cells, collectively migrates from the embryonic organizer to the animal pole, contributing to the elongation of the body axis in developing embryos like zebrafish and Xenopus.
Another example in embryonic development is the migration of neural crest cells. These cells originate from the developing neural tube and migrate throughout the embryo in cohesive chains or streams. Their movement is guided by chemical signals, such as the chemokine SDF1, which attracts them towards specific destinations where they differentiate into various tissues and organs, including parts of the nervous system and facial structures. This coordinated movement allows cells to form complex tissues and organs.
Beyond development, collective cell migration is also important for tissue repair, particularly in wound healing. When skin is injured, epithelial cells, specifically keratinocytes, collectively migrate as a cohesive sheet to close the wound, a process known as re-epithelialization. These cells detach from the underlying basal membrane at the wound edge and proliferate, extending a new epithelial layer over the damaged area. During this process, cells maintain their physical connections through E- and P-cadherin, ensuring the integrity of the migrating sheet.
Collective cell migration also contributes to the maintenance and regeneration of various tissues throughout an organism’s life. For example, the sprouting of new blood vessels, known as angiogenesis, involves collective migration of endothelial cells. These cells form cohesive strands that penetrate damaged or developing tissues to establish new vascular networks. This highlights how collective cell movement is employed for tissue remodeling.
When Collective Migration Goes Awry
While collective cell migration is beneficial, its dysregulation can contribute to diseases, particularly cancer. Cancer metastasis, the spread of cancer cells from a primary tumor to distant sites, can involve collective cell migration. Instead of detaching as individual cells, groups of cancer cells can collectively invade surrounding tissues and enter the bloodstream or lymphatic system.
These collectively migrating cancer cell clusters have advantages over single cells, including increased invasive capacity and enhanced resistance to chemotherapy treatments. Such clusters, known as circulating tumor cell (CTC) clusters, have been detected in the blood of cancer patients, even in early stages of the disease, and are associated with a poorer prognosis. The coordinated movement of these clusters allows them to navigate complex tissue environments.
In the context of cancer invasion, leader cells at the front of these collectives guide the movement into new territories. These leader cells display specific characteristics, such as enhanced protrusive activity and the ability to remodel the extracellular matrix. The follower cells are pulled along, contributing to the bulk movement and survival of the cluster. This collective behavior represents a challenge in cancer treatment, as it allows tumors to establish secondary sites.