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

TLDR

Cell migration through solid tissue often requires large nuclear deformations, yet the biological significance of this remains largely unclear. The study investigates how variations in the nucleoskeletal protein lamin‑A influence cell sorting and survival during migration through constraining micropores. Because A‑ and B‑type lamins confer viscous and elastic stiffness to the nucleus, subpopulations with differing A:B ratios sort during 3D migration. Lamin‑A is rate‑limiting for 3D migration across diverse human cells, with high lamin‑A:B ratios producing extruded nuclei and a biphasic effect where normal levels protect against stress‑induced death while knockdown impairs stress resistance; in vivo xenografts confirm A:B‑dependent sorting and enhanced tumor growth at intermediate ratios, demonstrating that lamins impede migration yet promote survival under migration‑induced stress.

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 after migration. Because the juxtaposed A and B polymer assemblies respectively conferred viscous and elastic stiffness to the nucleus, subpopulations with different A:B levels sorted in 3D migration. However, net migration was also biphasic in lamin-A, as wild-type 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.