Kyoto Study Reveals How Cells Coordinate During Collective Cell Migration

Like schools of fish and flocks of birds, cells often migrate as a coordinated group—a behavior that underpins embryonic development, wound healing, and the spread of cancer. Yet because individual cells can only sense limited local information, how they coordinate at the larger scale has remained unclear.

A team at Kyoto University now reports a molecular mechanism that helps connect the dots. Using live-cell imaging of Madin-Darby canine kidney (MDCK) cells, a common model in mammalian cell biology, the researchers tracked how a familiar adhesion protein, ZO-1, shifts location during group movement—and how it appears to help coordinate the cells around it.

Previous studies had pointed to adhesion between cells and waves of ERK signaling activation (named for the ERK proteins involved) as key components of collective migration. ZO-1, a scaffolding protein best known for its role in cell-cell adhesion, had also been suggested as a player. The Kyoto group set out to clarify how these pieces fit together.

The team observed cell migration directly while simultaneously monitoring ERK activity using a FRET biosensor and tracking ZO-1 with a fluorescent tag. Their analysis showed that ERK activation propagates through the cell population in waves, and that these waves prompt ZO-1 to relocate to podosomes—structures found on the basal cell surface. In effect, ZO-1 rides the ERK activation waves to those structures.

Once at the podosomes, ZO-1 enhanced force generation, supported extracellular matrix degradation, and drove invasive cell migration. ZO-1 itself also appeared to shape the dynamics of ERK activation, suggesting it acts as a regulator linking the way cell collectives coordinate their movement with the way individual cells invade their surroundings.

"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," said Sayuki Hirano, first author of the study published in Nature Communications.

By providing a molecular bridge between collective movement and tissue invasion, the findings could deepen understanding of both normal processes—such as development and wound healing—and pathological ones, including collective cancer invasion. The team next plans to test whether the same ZO-1 relocation observed in cultured cells also occurs in living tissues, and to identify the molecular mechanism through which ERK signaling controls where ZO-1 ends up.