Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Bell, Emily; Shah, Pragya; Zuela-Sopilniak, Noam; Kim, Dongsung; McGregor, Alexandra; Isermann, Philipp; Davidson, Patricia M.; Elacqua, Joshua J.; Lakins, Jonathan N.; Vahdat, Linda T.; Weaver, Valerie M.; Smolka, Marcus B.; Span, P.N.; Lammerding, Jan

doi:10.1101/2021.07.12.451842

Cited by 11 publications

(10 citation statements)

References 185 publications

(254 reference statements)

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“…A previous study found that overexpression of Akt resulted in a more than 4-fold increase of lamin A in interphase cells, but a 50% decrease in lamin A expression in mitotic cells ( Bertacchini et al, 2013 ). In recent experiments with MDA-MB-231 cells, we found that Akt inhibition resulted in a significant increase in lamin A/C protein levels, without changing LMNA gene expression ( Bell et al, 2021 ). Thus, it remains to be investigated if and how Akt may mediate effects of ATM inhibition on lamin A/C protein levels.…”

Section: Discussionmentioning

confidence: 99%

ATM Modulates Nuclear Mechanics by Regulating Lamin A Levels

Shah

McGuigan

Cheng

et al. 2022

Front. Cell Dev. Biol.

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Ataxia-telangiectasia mutated (ATM) is one of the three main apical kinases at the crux of DNA damage response and repair in mammalian cells. ATM activates a cascade of downstream effector proteins to regulate DNA repair and cell cycle checkpoints in response to DNA double-strand breaks. While ATM is predominantly known for its role in DNA damage response and repair, new roles of ATM have recently begun to emerge, such as in regulating oxidative stress or metabolic pathways. Here, we report the surprising discovery that ATM inhibition and deletion lead to reduced expression of the nuclear envelope protein lamin A. Lamins are nuclear intermediate filaments that modulate nuclear shape, structure, and stiffness. Accordingly, inhibition or deletion of ATM resulted in increased nuclear deformability and enhanced cell migration through confined spaces, which requires substantial nuclear deformation. These findings point to a novel connection between ATM and lamin A and may have broad implications for cells with ATM mutations—as found in patients suffering from Ataxia Telangiectasia and many human cancers—which could lead to enhanced cell migration and increased metastatic potential.

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Section: Discussionmentioning

confidence: 99%

ATM Modulates Nuclear Mechanics by Regulating Lamin A Levels

Shah

McGuigan

Cheng

et al. 2022

Front. Cell Dev. Biol.

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“…[ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] Lamin A/C, and not lamin B1, limits the passage of the nucleus through confining pores in 3D collagen gels or microfabricated microchannels. [ 19 , 20 ] Furthermore, the depletion of lamin A/C but not lamin B1 significantly softens the nucleus. [ 21 ] These studies collectively suggest that the mechanical stiffness conferred onto the nucleus by lamin A/C impedes nuclear deformation and hence cell passage through narrow micropores or channels.…”

Section: Introductionmentioning

confidence: 99%

The Nucleus Bypasses Obstacles by Deforming Like a Drop with Surface Tension Mediated by Lamin A/C

et al. 2022

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Migrating cells must deform their stiff cell nucleus to move through pores and fibers in tissue. Lamin A/C is known to hinder cell migration by limiting nuclear deformation and passage through confining channels, but its role in nuclear deformation and passage through fibrous environments is less clear. Cell and nuclear migration through discrete, closely spaced, slender obstacles which mimic the mechanical properties of collagen fibers are studied. Nuclei bypass slender obstacles while preserving their overall morphology by deforming around them with deep local invaginations of little resisting force. The obstacles do not impede the nuclear trajectory and do not cause rupture of the nuclear envelope. Nuclei likewise deform around single collagen fibers in cells migrating in 3D collagen gels. In contrast to its limiting role in nuclear passage through confining channels, lamin A/C facilitates nuclear deformation and passage through fibrous environments; nuclei in lamin‐null ( Lmna −/− ) cells lose their overall morphology and become entangled on the obstacles. Analogous to surface tension‐mediated deformation of a liquid drop, lamin A/C imparts a surface tension on the nucleus that allows nuclear invaginations with little mechanical resistance, preventing nuclear entanglement and allowing nuclear passage through fibrous environments.

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“…Evidence implicates LMNA/C in preserving nuclear integrity in ovarian epithelial cancer subtypes [ 88 ] and non-small-cell lung carcinoma cells [ 79 ]. Accordingly, lower LMNA/C levels in invasive breast cancer cells confer increased nuclear deformations enabling enhanced cell invasiveness [ 89 ]. Recent implications of LMNA/C in the p53/p16 INK4A senescence pathway [ 80 ] suggest an interplay between chromatin and signaling functions modulated by A-type lamins which will be worth investigating more closely.…”

Section: Discussionmentioning

confidence: 99%

Restructuring of Lamina-Associated Domains in Senescence and Cancer

Bellanger

Madsen-Østerbye

Galigniana

et al. 2022

Cells

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Induction of cellular senescence or cancer is associated with a reshaping of the nuclear envelope and a broad reorganization of heterochromatin. At the periphery of mammalian nuclei, heterochromatin is stabilized at the nuclear lamina via lamina-associated domains (LADs). Alterations in the composition of the nuclear lamina during senescence lead to a loss of peripheral heterochromatin, repositioning of LADs, and changes in epigenetic states of LADs. Cancer initiation and progression are also accompanied by a massive reprogramming of the epigenome, particularly in domains coinciding with LADs. Here, we review recent knowledge on alterations in chromatin organization and in the epigenome that affect LADs and related genomic domains in senescence and cancer.

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Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Cited by 11 publications

References 185 publications

ATM Modulates Nuclear Mechanics by Regulating Lamin A Levels

ATM Modulates Nuclear Mechanics by Regulating Lamin A Levels

The Nucleus Bypasses Obstacles by Deforming Like a Drop with Surface Tension Mediated by Lamin A/C

Restructuring of Lamina-Associated Domains in Senescence and Cancer

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