Cellular Energy Cycle Mediates an Advection‐Like Forward Cell Flow to Support Collective Invasion

Collective cell migration is a model for nonequilibrium biological dynamics, which is important for morphogenesis, pattern formation, and cancer metastasis. The current understanding of cellular collective dynamics is based primarily on cells moving within a 2D epithelial monolayer. However, solid tumors often invade surrounding tissues in the form of a stream‐like 3D structure, and how biophysical cues are integrated at the cellular level to give rise to this collective streaming remains unclear. Here, it is shown that cell cycle‐mediated bioenergetics drive a forward advective flow of cells and energy to the front to support 3D collective invasion. The cell division cycle mediates a corresponding energy cycle such that cellular adenosine triphosphate (ATP) energy peaks just before division. A reaction–advection–diffusion (RAD) type model coupled with experimental measurements further indicates that most cells enter an active division cycle at rear positions during 3D streaming. Once the cells progress to a later stage toward division, the high intracellular energy allows them to preferentially stream toward the tip and become leader cells. This energy‐driven cellular flow may be a fundamental characteristic of 3D collective dynamics based on thermodynamic principles important for not only cancer invasion but also tissue morphogenesis. During 3D collective streaming, cells at the rear are more likely to enter an active cell cycle which also corresponds to a progressive increase in cellular adenosine triphosphate (ATP) energy. Once the cells progress to a later stage of the cell cycle toward cell division, the high intracellular energy allows them to preferentially stream toward the tip and become leader cells.