Weak Volume-Surface Coupling as a Dynamic Descriptor of Efficient Cell Migration under Physical Confinement

Cancer cell invasion through physically confined spaces is governed by the biophysical interplay between morphological plasticity and mechanical constraints. A fundamental but unresolved question is how cells sustain efficient movement under such confinement without compromising their global volume homeostasis. Here, using a Matrigel-overlay quasi-three-dimensional system, we show that confinement-enhanced migration does not arise from static structural changes, but from a reorganization of volume-surface dynamics accompanied by changes in cellular mechanical state. To quantify this reorganization, we introduce a volume-surface dynamic correlation coefficient, C. This metric decreases significantly during confined migration, indicating a state of weak coupling between volume regulation and surface remodeling. Perturbations of processes essential for both motility and volume homeostasis consistently increase C, despite affecting cell behavior through distinct routes. Together, these findings identify weak volume-surface coupling as a dynamic descriptor of efficient migration under confinement.