Nuclear lamin stiffness is a barrier to 3D-migration, but softness can limit survival

Abstract

Cell migration through solid tissue often involves large contortions of the nucleus, but biological significance is largely unclear. The nucleoskeletal protein lamin-A varies both within and between cell types and was shown here to contribute to cell sorting and survival in migration through constraining micropores. Lamin-A proved rate-limiting in 3D-migration of diverse human cells that ranged from glioma and adenocarcinoma lines to primary mesenchymal stem cells (MSCs). Stoichiometry of A- to B-type lamins established an activation barrier, with high lamin-A:B producing extruded nuclear shapes post-migration. Because the juxtaposed A, B polymer assemblies respectively conferred viscous and elastic stiffness to the nucleus, sub-populations with different A:B levels sorted in 3D-migration. However, net migration was also biphasic in lamin-A, as wildtype lamin-A levels protected against stress-induced death, whereas deep knockdown caused broad defects in stress-resistance. In vivo xenografts proved consistent with A:B-based cell sorting, and intermediate A:B enhanced tumor growth. Lamins thus impede 3D migration but also promote survival against migration-induced stresses.