Cell strain-stiffening drives cell breakout from embedded spheroids.

Area of Science:

• Biophysics
• Cellular Mechanics
• Computational Biology

Background:

• Cellular escape from spheroids is crucial for understanding tissue development and disease.
• Existing models lack a detailed mechanical framework linking intracellular, intercellular, and cell-extracellular matrix (ECM) stresses.

Purpose of the Study:

• To develop a 3D mechanical framework for quantifying cell-level stress within spheroids.
• To investigate the relationship between cell mechanics, spheroid properties, and invasion modes.

Main Methods:

• Coupling a 3D vertex model of spheroids with a fibrous ECM network.
• Deriving a 3D Cauchy stress tensor for deformable polyhedral cells.
• Introducing an extended 3D vertex model with tunable cell-cell adhesion springs.

Main Results:

• Developed a framework for direct, 3D cell-level stress quantification.
• Solid-like spheroids show broader stress distributions; fluid-like spheroids exhibit lower, disorganized stresses.
• Demonstrated single-cell strain stiffening, where elongation nonlinearly increases shear stress.
• Identified mechanical conditions for single-cell breakout (strain stiffening + reduced adhesion) and multi-cell streaming (anisotropic adhesion).

Conclusions:

• Cell shape anisotropy is not a reliable indicator of mechanical state.
• Strain stiffening at the single-cell level can drive matrix remodeling and invasion.
• Distinct mechanical pathways involving cell strain, stress amplification, and adhesion govern spheroid invasion modes.