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

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

doi:10.1038/s41388-022-02420-9

Cited by 62 publications

(33 citation statements)

References 131 publications

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“…Subsequently, Young's modulus, as quantitative indices of cell stiffness, was reduced in lamin A/C or vimentindepleted cells (Figure 3B−D), suggesting that cell stiffness decreased and cells became soft. 19,32 Moreover, lamin A/C deficient cells were softer than vimentin deficient cells (Figure 3D), which may be because both lamin A/C and vimentin were simultaneously reduced in lamin A/C deficient cells, while lamin A/C increased in vimentin deficient cells (Figure 3A and Figure S2A in Supporting Information). In addition, we found that ectopic expression of vimentin significantly blocked the effect of lamin A/C deletion, similar to the role of re-expression of lamin A/C in endogenous lamin A/C depleted cells (Figure 3D).…”

Section: ■ Lamin A/c and Vimentin Synergistically Regulate Confinemen...mentioning

confidence: 99%

“…In vivo, invasive cancer cells need to migrate through small interstitial spaces formed by neighboring cells and the extracellular matrix. ,, To investigate the effect of physical constraints on cell migration, we developed a cell squeeze system with precisely adjustable degrees of confinement based on a six-well plate combined with controllable cell adhesion strength by chemical modifications, reconstituting the confined microenvironments in vivo . As displayed in Figure , we fabricated micropillars with precisely controlled heights based on soft photolithography to make the PDMS confinement slides.…”

Section: Confinement Induces the Reduction Of Lamin A/c Expression Pr...mentioning

confidence: 99%

“…Vimentin, another intermediate filament protein, forms a cage-like structure around the nucleus and modulates nuclear shape in response to mechanical forces. , Furthermore, the linkages between vimentin and lamin A/C are required for the reversibility of nuclear deformation . While the functions of lamin A/C and vimentin in mesenchymal cell migration have been extensively investigated, ,,− their roles in the context of confined-induced amoeboid migration are not yet clear.…”

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Lamin A/C and Vimentin as a Coordinated Regulator during Amoeboid Migration in Microscale Confined Microenvironments

et al. 2023

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Cell migration occurs in confined microenvironments, which plays a vital role in the process of tumor metastasis. However, it is challenging to study their behaviors in vivo. Here we developed a cell squeeze system that can be scaled down to micrometers to mimic native physical confined microenvironments, wherein degrees of surface adhesion and mechanical constraints could be manipulated in order to investigate cell-migrating behaviors. Based on the microscale cell squeeze system, we found the synergistic role of lamin A/C and vimentin in cell transition and migration under strong confinement. The dynamic variations in lamin A/C and vimentin expression establish a positive feedback loop in response to confinement, effectively promoting amoeboid migration by modulating nuclear deformability while ensuring cell viability. This work shed light on modulating cell response to microenvironments by altering the expression of lamin A/C and/or vimentin, which may be a more efficient way of inhibiting cancer metastasis.

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Section: ■ Lamin A/c and Vimentin Synergistically Regulate Confinemen...mentioning

confidence: 99%

Section: Confinement Induces the Reduction Of Lamin A/c Expression Pr...mentioning

confidence: 99%

mentioning

confidence: 99%

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Lamin A/C and Vimentin as a Coordinated Regulator during Amoeboid Migration in Microscale Confined Microenvironments

et al. 2023

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“…Remarkably, nuclear morphology plays a vital role in modulating cell fate in the continuum of cancer progression (Capo-Chichi et al, 2016;Smith et al, 2018;Fischer, 2020). In particular, the loss of emerin and lamin A show aberrations in nuclear morphology, accompanied by an increased aggressiveness of cancer cells (Reis-Sobreiro et al, 2018;Bell et al, 2022). Consistent with this finding, ovarian cancers show decreased emerin and lamin A/C levels, accompanied by a progressive destabilization of the nuclear envelope (Capochichi et al, 2011).…”

Section: Role Of Aberrant Nuclear Envelope Factors In Cancersmentioning

confidence: 88%

Nuclear envelope, chromatin organizers, histones, and DNA: The many achilles heels exploited across cancers

Balaji

Saha

Deshpande

et al. 2022

Front. Cell Dev. Biol.

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In eukaryotic cells, the genome is organized in the form of chromatin composed of DNA and histones that organize and regulate gene expression. The dysregulation of chromatin remodeling, including the aberrant incorporation of histone variants and their consequent post-translational modifications, is prevalent across cancers. Additionally, nuclear envelope proteins are often deregulated in cancers, which impacts the 3D organization of the genome. Altered nuclear morphology, genome organization, and gene expression are defining features of cancers. With advances in single-cell sequencing, imaging technologies, and high-end data mining approaches, we are now at the forefront of designing appropriate small molecules to selectively inhibit the growth and proliferation of cancer cells in a genome- and epigenome-specific manner. Here, we review recent advances and the emerging significance of aberrations in nuclear envelope proteins, histone variants, and oncohistones in deregulating chromatin organization and gene expression in oncogenesis.

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“…In addition, It has been observed that lamin A is either upregulated or downregulated in various types of cancer [11], contributing to the deterioration of nuclear biophysics and mechanically over-softened or over-stiffened response. These deviations significantly impact cell vitality and activity during transmigration through confined spaces [12][13][14][15][16], endothelial gaps [17] and the bloodstream [18]. The significance of these physical phenomena has sparked an interest in utilizing mathematical models and simulations to better comprehend nuclear deformation during related processes.…”

Section: Introductionmentioning

confidence: 99%

Microstructure-Based Nuclear Lamina Constitutive Model

Mostafazadeh¹,

Peng²

2023

Preprint

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The nuclear lamina is widely recognized as the most crucial component in providing mechanical stability to the nucleus. However, modeling the diverse mechanical aspects of this protein network still poses a significant challenge. We developed a constitutive model for the nuclear lamina network based on its microstructure, which accounts for the deformation phases at the dimer level, as well as the orientational arrangement and density of lamin filaments. Instead of relying on homology structure, we conducted molecular simulations to record the force-extension response of a highly accurate lamin dimer structure obtained through X-ray diffraction crystallography experimentation. Furthermore, we devised a semi-flexible worm-like chain extension-force model as a substitute for the multilinear equation, incorporating the stretching of the backbone, uncoiling of the dimer coiled-coil, and unfolding of alpha helices. Subsequently, we implemented our extension-force equation within a 2D network continuum model for the nuclear lamina and derived stress resultants. This enabled us to integrate the nuclear lamina into finite element simulations of the entire nucleus. Finally, we conducted simulations of nucleus endothelial transmigration, investigating the impact of varying network density and uncoiling constants on the critical force required for successful transmigration. The model allows us to incorporate the microstructure characteristics of the nuclear lamina into nucleus-related finite element modeling, thereby gaining insights into how laminopathies and mutations affect nuclear mechanics.

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

Cited by 62 publications

References 131 publications

Lamin A/C and Vimentin as a Coordinated Regulator during Amoeboid Migration in Microscale Confined Microenvironments

Lamin A/C and Vimentin as a Coordinated Regulator during Amoeboid Migration in Microscale Confined Microenvironments

Nuclear envelope, chromatin organizers, histones, and DNA: The many achilles heels exploited across cancers

Microstructure-Based Nuclear Lamina Constitutive Model

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