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

Harada, Takamasa; Swift, Joe; Irianto, Jerome; Shin, Jae Won; Spinler, Kyle R.; Athirasala, Avathamsa; Diegmiller, Rocky; Dingal, P.C. Dave P.; Ivanovska, Irena L.; Discher, Dennis E.

doi:10.1083/jcb.201308029

Cited by 535 publications

(587 citation statements)

References 60 publications

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“…The nuclear lamina has likely evolved to protect the genome and enhance cell viability. Deep knockdown of lamin-A followed by constricted migration in our previous studies 5 indeed resulted in enhanced cell death by mechanism(s) consistent with DNA damage.…”

Section: Introductionsupporting

confidence: 62%

“…However, at the bottom of Transwell membranes with highly constrictive micro-pores (3 µm diameter pores) 5 , migration causes damage to both repair of DSBs caused by ionizing radiation. Nuclear blebs with compromised lamina structure are also observed in cells expressing low levels of GFP-Lamin-A…”

Section: Resultsmentioning

confidence: 99%

“…Nuclear stiffness has long been speculated to limit a cell's ability to migrate through more small, stiff pores, and our recent studies of cancer cells 5 indeed showed that partial knockdown of lamin-A softened nuclei several-fold, enhanced constricted migration of cancer cells by several-fold, and also promoted more rapid invasion in vivo of nearby normal tissue. Similar studies of others likewise showed enhanced migration in vitro 3,19 .…”

Section: Introductionmentioning

confidence: 89%

“…Partial knock-down of Lamin-A in A549 cells were achieved by using shLMNA as described previously 5 . 256 lac operator repeats were integrated to the p-end of chromosome 1 of U2OS cells used in this study.…”

Section: Cell Culturementioning

confidence: 99%

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Constricted cell migration causes nuclear lamina damage, DNA breaks, and squeeze-out of repair factors

Irianto

Xia

et al. 2015

Preprint

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Genomic variation across cancers scales with tissue stiffness: meta-analyses show tumors in stiff tissues such as lung and bone exhibit up to 100-fold more variation than tumors in soft tissues such as marrow and brain. Here, nuclear lamina damage and DNA double-strand breaks (DSBs) result (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Introductionsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Cell Culturementioning

confidence: 99%

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Constricted cell migration causes nuclear lamina damage, DNA breaks, and squeeze-out of repair factors

Irianto

Xia

et al. 2015

Preprint

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“…7 Confined migration causes increased nuclear envelope rupture While earlier studies were limited to cells in 2D culture, researchers have recently begun to investigate the role of the nucleus in 3D cell migration and uncovered that nuclear deformation can become a rate-limiting factor during confined migration. [13][14][15][16][17][18] When cells encounter constrictions smaller than the nuclear cross section, the large and relatively rigid nucleus must deform substantially to pass through the available space. 13,14,19 Two recent studies found that the forces exerted on the nucleus during this process frequently rupture the NE.…”

Section: Introductionmentioning

confidence: 99%

Consequences of a tight squeeze: Nuclear envelope rupture and repair

Isermann

Lammerding

2017

Nucleus

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Cell migration through tight spaces can induce substantial deformations of the nucleus and cause nuclear envelope (NE) rupture, resulting in uncontrolled exchange of nuclear and cytosolic proteins. These events can cause DNA damage and, in severe cases, nuclear fragmentation, challenging the integrity of the genomic material. Cells overcome NE ruptures during interphase by repairing the NE using components of the endosomal sorting complexes required for transport (ESCRT) machinery. Paralleling the molecular mechanism used during NE reformation in late mitosis, ESCRT-III subunits and the associated AAA-ATPase VPS4B are recruited to NE rupture sites and help restore NE integrity. While these findings are common to many cell types, they are particularly relevant in the context of cancer metastasis, where nuclear deformation and rupture could drive genomic instability in invading cells and further promote cancer progression. At the same time, inhibiting NE repair may offer new therapeutic approaches to specifically target invasive cancer cells.

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Scaffold, mechanics and functions of nuclear lamins

Buxboim,

Kronenberg‐Tenga,

Salajkova

et al. 2023

FEBS Letters

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Nuclear lamins are type‐V intermediate filaments that are involved in many nuclear processes. In mammals, A‐ and B‐type lamins assemble into separate physical meshwork underneath the inner nuclear membrane, the nuclear lamina, with some residual fraction localized within the nucleoplasm. Lamins are the major part of the nucleoskeleton, providing mechanical strength and flexibility to protect the genome and allow nuclear deformability, while also contributing to gene regulation via interactions with chromatin. While lamins are the evolutionary ancestors of all intermediate filament family proteins, their ultimate filamentous assembly is markedly different from their cytoplasmic counterparts. Interestingly, hundreds of genetic mutations in the lamina proteins have been causally linked with a broad range of human pathologies, termed laminopathies. These include muscular, neurological and metabolic disorders, as well as premature aging diseases. Recent technological advances have contributed to resolving the filamentous structure of lamins and the corresponding lamina organization. In this review, we revisit the multiscale lamin organization and discuss its implications on nuclear mechanics and chromatin organization within lamina‐associated domains.

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

Abstract: Lamins impede 3D migration but also promote survival against migration-induced stresses.

Cited by 535 publications

References 60 publications

Constricted cell migration causes nuclear lamina damage, DNA breaks, and squeeze-out of repair factors

Constricted cell migration causes nuclear lamina damage, DNA breaks, and squeeze-out of repair factors

Consequences of a tight squeeze: Nuclear envelope rupture and repair

Scaffold, mechanics and functions of nuclear lamins

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