Activating the nuclear piston mechanism of 3D migration in tumor cells

Petrie, Ryan J.; Harlin, Heather M.; Korsak, Lulu I T.; Yamada, Katsushi

doi:10.1083/jcb.201605097

Cited by 94 publications

(96 citation statements)

References 27 publications

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“…However, other studies have shown that expression of integrin β3 is variable in response to other forms of mechanical stimuli in various types of cancer (Felding-Habermann et al, 2001;Page et al, 2015). Additionally, a recent study found that HT1080 cells exhibit an MMP-independent 'nuclear piston' mechanism of invasion that requires integrin β3 activity (Petrie et al, 2017). It is an intriguing possibility that a cell uses the expression of integrin β3 to select between modes of invasion, such that downregulation promotes MMP-dependent invasion while normal levels of integrin β3 expression favors an MMPindependent nuclear piston mode of invasion.…”

Section: Discussionmentioning

confidence: 99%

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Gasparski

Ozarkar

Beningo

2017

Journal of Cell Science

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Cancer cell invasion is influenced by various biomechanical forces found within the microenvironment. We have previously found that invasion is enhanced in fibrosarcoma cells when transient mechanical stimulation is applied within an in vitro mechano-invasion assay. This enhancement of invasion is dependent on cofilin (CFL1), a known regulator of invadopodia maturation. Invadopodia are actin-rich structures present in invasive cancer cells that are enzymatically active and degrade the surrounding extracellular matrix to facilitate invasion. In this study, we examine changes in gene expression in response to tugging on matrix fibers. Interestingly, we find that integrin β3 expression is downregulated and leads to an increase in cofilin activity, as evidenced by a reduction in its Ser3 phosphorylation levels. As a result, invadopodia lengthen and have increased enzymatic activity, indicating that transient mechanical stimulation promotes the maturation of invadopodia leading to increased levels of cell invasion. Our results are unique in defining an invasive mechanism specific to the invasive process of cancer cells that is triggered by tugging forces in the microenvironment, as opposed to rigidity, compression or stretch forces.

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Section: Discussionmentioning

confidence: 99%

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Gasparski

Ozarkar

Beningo

2017

Journal of Cell Science

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“…Increased heterochromatin levels were shown to increase nuclear rigidity (Zhang et al 2016a;Furusawa et al 2015;Stephens et al 2018), which may be important to protect the genome from mechanical damage that can occur during migration through confined spaces (Denais et al 2016;Raab et al 2016). Increased nuclear rigidity may also serve as a better anchoring point for the actin cytoskeleton that was suggested to use the nucleus to generate force during cell migration (Graham et al 2018;Petrie et al 2017). In support of the at 37 O C, 7% CO2.…”

Section: Discussionmentioning

confidence: 77%

The heterochromatin landscape in migrating cells and the importance of H3K27me3 for migration-associated transcriptional changes

Segal

Salmon‐Divon

Gerlitz

2018

Preprint

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SummaryH3K9me3, H3K27me3 and H4K20me1 are epigenetic markers associated with chromatin condensation and transcriptional repression. Previously, we found that migration of melanoma cells is associated with and dependent on global chromatin condensation that includes a global increase in these markers. Taken together with more recent reports by others suggest it is a general signature of migrating cells. Here, to learn about the function of these markers in migrating cells we mapped them by ChIP-seq analysis. This analysis revealed that induction of migration leads to expansion of these markers along the genome and to an increased overlapping between them. Significantly, induction of migration led to a higher increase in H3K9me3 and H4K20me1 signals at repetitive elements than at protein-coding genes, while an opposite pattern was found for H3K27me3. Transcriptome analysis revealed that 182 altered genes following induction of migration, of which 33% are dependent on H3K27me3 for these changes. H3K27me3 was also required to prevent changes in the expression of 501 other genes upon induction of migration. Taken together our results suggest that heterochromatinization in migrating cells is global and not restricted to specific genomic loci and that H3K27me3 is a key component in executing a migration-specific transcriptional plan.

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“…The malignant counterpart of normal human fibroblasts, fibrosarcoma cells, fails to undergo nuclear piston migration in a cell‐derived matrix until their protease activity is inhibited for stabilization of the adjacent extracellular matrix . In fact, treatment of cell‐derived matrix with proteases can abolish lobopodial migration by normal human fibroblasts .…”

Section: Cancermentioning

confidence: 99%

Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis

Yamada

Collins

Walma

et al. 2019

Int J Experimental Path

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This review describes how direct visualization of the dynamic interactions of cells with different extracellular matrix microenvironments can provide novel insights into complex biological processes. Recent studies have moved characterization of cell migration and invasion from classical 2D culture systems into 1D and 3D model systems, revealing multiple differences in mechanisms of cell adhesion, migration and signalling-even though cells in 3D can still display prominent focal adhesions.Myosin II restrains cell migration speed in 2D culture but is often essential for effective 3D migration. 3D cell migration modes can switch between lamellipodial, lobopodial and/or amoeboid depending on the local matrix environment. For example, "nuclear piston" migration can be switched off by local proteolysis, and proteolytic invadopodia can be induced by a high density of fibrillar matrix. Particularly, complex remodelling of both extracellular matrix and tissues occurs during morphogenesis. Extracellular matrix supports self-assembly of embryonic tissues, but it must also be locally actively remodelled. For example, surprisingly focal remodelling of the basement membrane occurs during branching morphogenesis-numerous tiny perforations generated by proteolysis and actomyosin contractility produce a microscopically porous, flexible basement membrane meshwork for tissue expansion. Cells extend highly active blebs or protrusions towards the surrounding mesenchyme through these perforations. Concurrently, the entire basement membrane undergoes translocation in a direction opposite to bud expansion. Underlying this slowly moving 2D basement membrane translocation are highly dynamic individual cell movements. We conclude this review by describing a variety of exciting research opportunities for discovering novel insights into cell-matrix interactions. K E Y W O R D S3D culture, basement membrane remodelling, branching morphogenesis, cell migration, extracellular matrix, invasion

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Activating the nuclear piston mechanism of 3D migration in tumor cells

Abstract: Petrie et al. show that inhibiting matrix metalloproteinases during 3D tumor cell migration activates the fibroblast-associated nuclear piston mechanism of intracellular pressure generation to slow tumor cell movement.

Cited by 94 publications

References 27 publications

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

The heterochromatin landscape in migrating cells and the importance of H3K27me3 for migration-associated transcriptional changes

Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis

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