BPS2026 – Role of nuclear motor proteins in nuclear mechanics and cell migration through confined spaces

Deformation of the nucleus often presents a barrier to cell migration through tight spaces such as those encountered as cells move through tissues or across extracellular matrix barriers. Reorganizing the nucleus to allow its passage through spaces smaller than its resting diameter requires forces generated by the cytoskeleton as well as active reorganization within the nucleus driven by ATPases that crosslink or move chromatin. Two different nuclear ATPases, the BRG1/SMARCA4 motor of the BAF or SWI/SNF complex and the bifunctional crosslinking and loop extruding complex, cohesin, have opposite effects on the stiffness of nuclei. Inhibiting BRG1 stiffens the nucleus, and inhibiting cohesin softens it in karyoplasts derived from multiple cell types, including four different cancer cell lines, fibroblasts, and mesenchymal stem cells. The effects on isolated nuclear stiffness coincide with the effects of inhibiting these ATPases on the ability of cells to migrate through tight spaces. Stiffening the nucleus inhibits single cell migration through micron-sized pores and the outward migration of tumor cell spheroids into a surrounding collagen matrix. Softening the nucleus generally has the opposite effect: it enhances single-cell migration through pores and facilitates the outgrowth of cells from a tumor cell spheroid into the surrounding matrix. These results emphasize the importance of active motions generated within the nucleus for the global mechanics of the nucleus and the way that it deforms in response to externally generated stresses.