Mechanical Checkpoint for Cell Division in Three-Dimensional Microenvironments

Cell division within mechanically confining extracellular matrices (ECMs) is a key regulator of tissue morphogenesis and cancer progression. Although intracellular force-generation mechanisms driving volumetric growth and mitotic elongation are well characterized, how ECMs resist these forces remains poorly understood. Unlike linear elastic materials, fibrillar ECMs exhibit nonlinear and viscoelastic behaviors that alter how they oppose cell-generated stresses. Using a fiber-level computational model, we dissected the origins of ECM-mediated mechanical confinement during mitosis. We identified three modes of resistance: compressive resistance at cell poles, shear resistance from a pericellular shell, and tensile resistance at cell equator. The relative contributions of these modes depended on fiber architecture and connectivity; however, shear resistance from the pericellular shell-pre-tensed by volumetric growth during G1-consistently dominated as the primary mechanical barrier to mitotic elongation. These findings suggest that the pericellular shell functions as a mechanical checkpoint on cell division within collagen-rich microenvironments. We propose that overcoming this mechanical checkpoint is a critical step in cancer progression, enabling cells to divide within the dense stromal matrices characteristic of metastatic tumors.