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Understanding how cells escape from embedded spheroids requires a mechanical framework that connects stress generation within cells, across cells, and between cells and the surrounding extracellular matrix (ECM). Here, we develop such a framework using a 3D vertex model of a spheroid coupled to a fibrous ECM network and derive the 3D Cauchy stress tensor for deformable polyhedral cells, enabling direct quantification of cell-level stresses in three dimensions beyond shape-based or bulk rheological measures. We characterize maximum shear stress distributions for solid-like and fluid-like spheroids. Solid-like spheroids exhibit broad stress distributions and spatial stress gradients, whereas fluid-like spheroids display lower stresses and minimal spatial patterning. We find little generic alignment between cell shape anisotropy and principal stress directions, demonstrating that morphology alone is not a reliable indicator of mechanical state. We further show that individual cells undergo strain stiffening upon elongation, producing nonlinear increases in maximum shear stress. This provides a mechanism by which boundary cells in otherwise low-stress, fluid-like spheroids can transiently generate forces sufficient to remodel the surrounding matrix. These results indicate that invasion cannot be understood solely through tissue-level unjamming transitions, but also involves cell-level stress amplification processes. To investigate how this strain-induced stress amplification couples to collective invasion modes, we introduce an extended 3D vertex model in which cells interact through explicit, tunable cell-cell adhesion springs. Within this minimal mechanical framework, single-cell breakout arises from the combination of strain stiffening and weakened cell-cell adhesion, whereas multi-cell streaming requires an additional ingredient: anisotropic adhesion strengthened along the axis of elongation in highly strained cells and weakened orthogonally. These findings identify distinct mechanical pathways linking cell strain, stress amplification, and adhesion organization to different modes of spheroid invasion.
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This content will become publicly available on June 18, 2027
Vimentin promotes collective cell migration through collagen networks via increased matrix remodeling and spheroid fluidity
Abstract Intermediate filaments (IF) are diverse and cell-type specific. The IF protein vimentin, expressed in mesenchymal cells and different cancer cells, is functionally associated with cell migration through fibrous tissues. Vimentin increases cell elongation needed for migration, yet also acts as a cytoskeletal cage that hinders cells squeezing through small spaces. To determine how vimentin facilitates cell migration through the extracellular matrix (ECM) and around neighboring cells in tissues, we examine the collective invasion of cell spheroids embedded in collagen networks. Unlike single-cell migration in collagen networks, the collective invasion of cells through the collagen network is increased by vimentin for both mouse embryonic fibroblasts (MEF) and co-cultures of MEF with MDA-MB-231 breast cancer cells. Using multiple experimental systems, we show that vimentin increases spheroid contractility and that vimentin-mediated collective cell expansion depends on matrix metalloproteinases (MMP), which degrade collagen networks. In addition, through advanced imaging and a computational 3D cell vertex model, we find that vimentin enhances the elongation of cells in spheroids embedded in collagen, indicating increased spheroid fluidity and active collagen contraction. Altogether, these results reveal new insights on vimentin’s effects in enhancing collective cell migration in 3D matrix environments through collagen remodeling and tissue fluidity.
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- Award ID(s):
- 2412961
- PAR ID:
- 10697923
- Publisher / Repository:
- Springer Nature
- Date Published:
- Journal Name:
- Communications Biology
- ISSN:
- 2399-3642
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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