Enhanced mechanical heterogeneity of cell collectives due to temporal fluctuations in cell elasticity.

Cells are dynamic systems characterized by temporal variations in biophysical properties such as stiffness and contractility. Recent studies show that the recruitment and release of actin filaments into and out of the cell cortex-a network of proteins underneath the cell membrane-leads to cell stiffening prior to division and softening immediately afterward. In three-dimensional (3D) cell collectives, it is unclear whether the stiffness change during division at the single-cell scale controls the spatial structure and dynamics at the multicellular scale. This is an important question to understand because cell stiffness variations impact cell spatial organization and cancer progression. Using a minimal 3D model incorporating cell birth, death, and cell-to-cell elastic and adhesive interactions, we investigate the effect of mechanical heterogeneity-variations in individual cell stiffnesses that make up the cell collective-on tumor spatial organization and cell dynamics. We discover that spatial mechanical heterogeneity characterized by a spheroid core composed of stiffer cells and softer cells in the periphery emerges within dense 3D cell collectives, which may be a general feature of multicellular tumor growth. We show that heightened spatial mechanical heterogeneity enhances single-cell dynamics and volumetric tumor growth driven by fluctuations in cell elasticity. Our results could have important implications in understanding how spatiotemporal variations in single-cell stiffness determine tumor growth and spread.

Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation.

Morphogenesis is governed by the interplay of molecular signals and mechanical forces across multiple length scales. The last decade has seen tremendous advances in our understanding of the dynamics of protein localization and turnover at subcellular length scales, and at the other end of the spectrum, of mechanics at tissue-level length scales. Integrating the two remains a challenge, however, because we lack a detailed understanding of the subcellular patterns of mechanical properties of cells within tissues. Here, in the context of the elongating body axis of Xenopus embryos, we combine tools from cell biology and physics to demonstrate that individual cell-cell junctions display finely-patterned local mechanical heterogeneity along their length. We show that such local mechanical patterning is essential for the cell movements of convergent extension and is imparted by locally patterned clustering of a classical cadherin. Finally, the patterning of cadherins and thus local mechanics along cell-cell junctions are controlled by Planar Cell Polarity signaling, a key genetic module for CE that is mutated in diverse human birth defects.