Understanding the mechanisms of collective cell movement

Like schools of fish and flocks of birds, our cells can also migrate collectively in coordination with their neighbors. This harmonious movement of cells occurs during embryonic development, wound healing, and cancer metastasis. However, since individual cells can only sense limited local information, how they are able to coordinate as a larger collective has remained poorly understood.

Previous studies have demonstrated that this collective migration involves adhesion between cells and waves of ERK signaling activation, named for the ERK proteins involved, and may also be influenced by ZO-1, a scaffolding protein best known for its role in cell-cell adhesion. Building on this knowledge, a team of researchers at Kyoto University was motivated to uncover the elusive mechanism behind collective cell movement.

Using live-cell imaging of Madin-Darby canine kidney cells—model mammal cells often used in biomedical studies—the researchers were able to directly observe the movement of cell collectives. They simultaneously monitored ERK activity using a FRET biosensor and visualized ZO-1 localization using fluorescently tagged ZO-1.

The team's analysis revealed that ERK activation propagates through the cell population and promotes the relocation of ZO-1 to podosomes, structures found on the basal cell surface, during collective cell migration. Effectively, ZO-1 rides ERK activation waves to the podosomes. Once there, the researchers observed that ZO-1 enhances force generation, extracellular matrix degradation, and invasive cell migration. The paper is published in the journal Nature Communications.

The team also discovered that ZO-1 itself contributes to the dynamics of ERK activation, suggesting that it acts as a regulator by linking two important aspects of cell behavior: the mechanism by which cell collectives coordinate their movement, and the mechanism by which cells invade by degrading their surrounding environment. In providing a molecular connection between these processes, the researchers expect these findings to contribute to a better understanding of normal biological processes, such as development and wound healing, as well as collective cancer invasion.

"I found it particularly fascinating that ZO-1, which is generally understood as a protein that functions in cell to cell adhesion, can move to podosomes at the basal cell surface depending on the state of the cell," says first author Sayuki Hirano.

In the future, the team aims to examine whether the dynamic relocation of ZO-1 they observed in cultured cells also occurs in living tissues. They also plan to investigate the molecular mechanism through which ERK signaling regulates ZO-1 localization.