The entropy of cancer cell migration: Bioenergetics and cell proliferation support invasive migration in 3D

Many cancer cells invade into the surrounding tissues in the form of a stream-like 3D collective structure, with distinct leader and follower cells. We previously demonstrated that leading cancer cells adopt a “drafting” strategy to efficiently overcome the barrier of migration imposed by the surrounding matrices. However, it is not clear how biophysical cues are integrated at follower positions to give rise to this collective streaming. Here, we show for the first time that energetic difference that arises from cell cycle progression drives forward motion of high-energy follower cells to the leader position to support 3D collective invasion. ATP energy, which powers numerous cellular processes, increases with cell cycle progression and peaks at the G2/M phase. With iterative experimental measurements and physical modeling based on a reaction-advection-diffusion framework, we demonstrated that the high energy in G2 cells drives their forward streaming dynamics to support 3D collective invasion, which also shifted the distribution of G2 cells toward the leader position. The accumulation or dissemination of high-energy G2 cells toward the leader position increases the disorder of cancer cell distribution thus increasing the “entropy” of the tumor-matrix system. Hence, this energy-driven cell streaming may be a fundamental characteristic of 3D collective dynamics governed by thermodynamic principles and may provide new insights to our understanding of not only cancer invasion but also tissue morphogenesis.