The morphodynamics of 3D migrating cancer cells

Cell shape is an important biomarker that is directly linked to cell function. However, cell morphodynamics, namely the temporal fluctuation of cell shape is much less understood. We study the morphodynamics of MDA-MB-231 cells in type I collagen extracellular matrix (ECM). We find ECM mechanics, as tuned by collagen concentration, controls the morphodynamics but not the static cell morphology. We employ machine learning to classify cell shape into five different morphological phenotypes corresponding to different migration modes. As a result, cell morphodynamics is mapped into temporal evolution of morphological phenotypes. We systematically characterize the phenotype evolutions including occurrence probability, dwell time, transition flux, and 3D migrational characteristics. We find that manipulating Rho-signaling enhances the morphodynamics and phenotype transitions. Using a tumor organoid model, we show that the distinct invasion potentials of each phenotype modulate the phenotype homeostasis. Overall invasion of a tumor organoid is facilitated by individual cells searching for and committing to phenotypes of higher invasive potential. In conclusion, we show that 3D migrating cancer cells exhibit rich morphodynamics that is regulated by ECM mechanics, Rho-signaling, and is closely related with cell motility. Our results pave the way to the systematic characterization and functional understanding of cell morphodynamics as a new biomarker for normal and malignant cells.