title: 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 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.
authors.affiliation: Molecular and Cell Biophysics Lab and 2 Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Harada
authors.forename: Joe
authors.initials: J
authors.lastname: Swift
authors.forename: Jerome
authors.initials: J
authors.lastname: Irianto
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Shin
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Spinler
authors.forename: Avathamsa
authors.initials: A
authors.lastname: Athirasala
authors.forename: Rocky
authors.initials: R
authors.lastname: Diegmiller
authors.forename: P C Dave P
authors.initials: PC
authors.lastname: Dingal
authors.forename: Irena L
authors.initials: IL
authors.lastname: Ivanovska
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000648:ultrastructure; D053144:Cell Nucleus Shape; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D034921:Lamin Type B / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary
chemical_list: D034904:Lamin Type A; D034921:Lamin Type B