Nuclear Stiffening Inhibits Migration of Invasive Melanoma Cells

Ribeiro, Alexandre J. S.; Khanna, Payal; Sukumar, Aishwarya; Dong, Chuan; Dahl, Kris Noel

doi:10.1007/s12195-014-0358-3

Cited by 35 publications

(38 citation statements)

References 54 publications

(75 reference statements)

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“…The maintenance of nuclear physical properties is also essential in cell migration during developmental programs (25) as well as in wound healing (26,27). Defects in nuclear morphology and its deformability have also been shown to be important in metastatic potential and cancer cell invasion (28). Further, a number of diseases have been associated with loss of the mechanical integrity of the nuclear lamina (29)(30)(31).…”

mentioning

confidence: 99%

Nuclear deformability and telomere dynamics are regulated by cell geometric constraints

Makhija

Jokhun

Shivashankar

2015

Proc. Natl. Acad. Sci. U.S.A.

190

186

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Forces generated by the cytoskeleton can be transmitted to the nucleus and chromatin via physical links on the nuclear envelope and the lamin meshwork. Although the role of these active forces in modulating prestressed nuclear morphology has been well studied, the effect on nuclear and chromatin dynamics remains to be explored. To understand the regulation of nuclear deformability by these active forces, we created different cytoskeletal states in mouse fibroblasts using micropatterned substrates. We observed that constrained and isotropic cells, which lack long actin stress fibers, have more deformable nuclei than elongated and polarized cells. This nuclear deformability altered in response to actin, myosin, formin perturbations, or a transcriptional down-regulation of lamin A/C levels in the constrained and isotropic geometry. Furthermore, to probe the effect of active cytoskeletal forces on chromatin dynamics, we tracked the spatiotemporal dynamics of heterochromatin foci and telomeres. We observed increased dynamics and decreased correlation of the heterochromatin foci and telomere trajectories in constrained and isotropic cell geometry. The observed enhanced dynamics upon treatment with actin depolymerizing reagents in elongated and polarized geometry were regained once the reagent was washed off, suggesting an inherent structural memory in chromatin organization. We conclude that active forces from the cytoskeleton and rigidity from lamin A/C nucleoskeleton can together regulate nuclear and chromatin dynamics. Because chromatin remodeling is a necessary step in transcription control and its memory, genome integrity, and cellular deformability during migration, our results highlight the importance of cell geometric constraints as critical regulators in cell behavior. mechanotransduction | cell geometry | actomyosin contractility | chromatin dynamics | telomere dynamics P hysical properties of the nucleus, such as its morphology and deformability, have been associated with important cellular functions like gene expression, genome integrity, and cell behavior (1-3). The major cellular components that regulate these physical properties are the cytoskeleton to nuclear links and the nuclear lamina (4-8). Lineage-specific physical properties of the nucleus emerge during cellular differentiation; although stem cell nuclei are highly deformable (9, 10) and have a dynamic chromatin with hyperdynamic chromatin proteins (11), with differentiation, nuclei lose their deformability and become less deformable (12). The nucleus in a differentiated cell is physically coupled to the cytoskeleton via lamins and the linker of nucleoskeleton and cytoskeleton (LINC) complex, which comprises transmembrane Sad1p, UNC-84 (SUN) and Klarsicht, ANC-1, Syne Homology (KASH) domain proteins (13-18). Any perturbation to these components is linked to changes in nuclear morphology and deformability (19). Therefore, the meshwork of actin stress fibers and lamin A/C serves as a critical physical intermediate in the maintenance of nuclear func...

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mentioning

confidence: 99%

Nuclear deformability and telomere dynamics are regulated by cell geometric constraints

Makhija

Jokhun

Shivashankar

2015

Proc. Natl. Acad. Sci. U.S.A.

190

186

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“…Although characterization of cytoskeleton deformation has been demonstrated using several techniques like optical stretcher50, the quantitative measurement of cell nuclear deformation has not been fully studied especially in a high throughput format. Current methods used in the study of deformability of cell nuclei include optical tweezers, micropipette aspiration, AFM-nanoindentation, microfluidics devices282930313251525354. (Sup.…”

mentioning

confidence: 99%

“…Human embryonic stem cells in terminal differentiation were found to become less deformable against micromanipulation and stiffen up to 6 times56. In a micropipette aspiration study, melanoma cell invasion slowed down after stiffening of the nuclei due to overexpression of a form of Lamin A that is found in diseased and aged cells54. The epithelial monolayers were exposed to mechanical strain and showed that actin and microtubules play a key role in nuclear deformations57.…”

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confidence: 99%

A high throughput approach for analysis of cell nuclear deformability at single cell level

Ermis

Akkaynak

Chen

et al. 2016

Sci Rep

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Various physiological and pathological processes, such as cell differentiation, migration, attachment, and metastasis are highly dependent on nuclear elasticity. Nuclear morphology directly reflects the elasticity of the nucleus. We propose that quantification of changes in nuclear morphology on surfaces with defined topography will enable us to assess nuclear elasticity and deformability. Here, we used soft lithography techniques to produce 3 dimensional (3-D) cell culture substrates decorated with micron sized pillar structures of variable aspect ratios and dimensions to induce changes in cellular and nuclear morphology. We developed a high content image analysis algorithm to quantify changes in nuclear morphology at the single-cell level in response to physical cues from the 3-D culture substrate. We present that nuclear stiffness can be used as a physical parameter to evaluate cancer cells based on their lineage and in comparison to non-cancerous cells originating from the same tissue type. This methodology can be exploited for systematic study of mechanical characteristics of large cell populations complementing conventional tools such as atomic force microscopy and nanoindentation.

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“…Methods to aspirate whole nuclei or cells containing whole nuclei have been used to characterize nuclear mechanical properties [18][19][20][21] , but because cytoskeletal structures and tension on the nucleus are absent in isolated and trypsinized cells respectively, these methods are not suited for probing nuclear-cytoskeletal coupling in spread adherent cells. Many years ago, Maniotis et al developed an approach to pull on the membrane of adherent cells with a micropipette tip, and recorded deformation and motion of the nucleus in response 22 .…”

Section: Mechanically Probing the Nucleus In The Cellmentioning

confidence: 99%

Dynamic, mechanical integration between nucleus and cell- where physics meets biology

Dickinson

Neelam

Lele

2015

Nucleus

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Nuclear motions like rotation, translation and deformation suggest that the nucleus is acted upon by mechanical forces. Molecular linkages with the cytoskeleton are thought to transfer forces to the nuclear surface. We developed an approach to apply reproducible, known mechanical forces to the nucleus in spread adherent cells and quantified the elastic response of the mechanically integrated nucleus-cell. The method is sensitive to molecular perturbations and revealed new insight into the function of the LINC complex. While these experiments revealed elastic behaviors, turnover of the cytoskeleton by assembly/disassembly and binding/unbinding of linkages are expected to dissipate any stored mechanical energy in the nucleus or the cytoskeleton. Experiments investigating nuclear forces over longer time scales demonstrated the mechanical principle that expansive/compressive stresses on the nuclear surface arise from the movement of the cell boundaries to shape and position the nucleus. Such forces can shape the nucleus to conform to cell shapes during cell movements with or without myosin activity.

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Nuclear Stiffening Inhibits Migration of Invasive Melanoma Cells

Cited by 35 publications

References 54 publications

Nuclear deformability and telomere dynamics are regulated by cell geometric constraints

Nuclear deformability and telomere dynamics are regulated by cell geometric constraints

A high throughput approach for analysis of cell nuclear deformability at single cell level

Dynamic, mechanical integration between nucleus and cell- where physics meets biology

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