(175y) The Excess Surface Area of the Nuclear Lamina Determines Whether Cells Can Migrate through Narrow Constrictions.

Cell migration through narrow interstitial spaces within tissues is a pivotal process implicated in diverse physiological and pathological scenarios, spanning from fibroblast migration to wound sites to the invasive behavior of metastatic cancer cells. The deformability of the cell nucleus, the largest organelle in cells, often constrains the ability of cells to migrate through constrictions, such as pores in fibrous tissue. Nuclear deformations in confinement can also lead to rupture of the nuclear envelope, inducing DNA damage and promoting oncogenic transformations. Our recent experimental and computational findings show that excess surface area of the stiff nuclear lamina for a given nuclear volume confers to the nucleus the property of being high compliant to cellular forces, much like a liquid drop, over a wide range of nuclear shapes, as long as the shapes do not require stretching of the lamina or compression of the nuclear volume. In this limit where further deformation of the confined nucleus would require compression of the nucleus or stretching of the nuclear lamina, then the lamina becomes smooth and taut, and the resulting nuclear shapes can be mathematically predicted from geometric constraints on surface area and volume. In the present work, we demonstrate that the shapes of nuclei during cell migration through narrow constrictions in a microfluidic device follow this principle and can be predicted using a computational model based on constraints on lamina surface area and nuclear volume. The model accurately predicts nuclear shapes observed in constricted environments, along with the minimum surface area required for nuclear transit through such constrictions for a given nuclear volume. These findings explain how the geometric and mechanical properties of the nucleus, specifically the surface area of the stiff nuclear lamina, limit cell migration through narrow constrictions.