An open access microfluidic device for the study of the physical limits of cancer cell deformation during migration in confined environments

Malboubi, Majid; Jayo, Asier; Parsons, Maddy; Charras, Guillaume

doi:10.1016/j.mee.2015.02.022

Cited by 28 publications

(24 citation statements)

References 9 publications

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“…Nuclear translocation through microchannels of different widths fits to a sigmoidal distribution in which the inflection point of the curve, where 50% of the cells translocate, can be used as a relative cut-off size for cell translocation. In accordance with our previously published data (Malboubi et al., 2015), control MDA MB 231 showed a cut-off size of 6.99 μm, while in fascin KD cells this increased to 9.77 μm. Conversely, stable expression of shRNA-resistant GFP-fascin induced a decrease in the cut-off size to 6.45 μm, close to the control levels (Figures S4E and S4F).…”

Section: Resultssupporting

confidence: 94%

Fascin Regulates Nuclear Movement and Deformation in Migrating Cells

et al. 2016

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SummaryFascin is an F-actin-bundling protein shown to stabilize filopodia and regulate adhesion dynamics in migrating cells, and its expression is correlated with poor prognosis and increased metastatic potential in a number of cancers. Here, we identified the nuclear envelope protein nesprin-2 as a binding partner for fascin in a range of cell types in vitro and in vivo. Nesprin-2 interacts with fascin through a direct, F-actin-independent interaction, and this binding is distinct and separable from a role for fascin within filopodia at the cell periphery. Moreover, disrupting the interaction between fascin and nesprin-2 C-terminal domain leads to specific defects in F-actin coupling to the nuclear envelope, nuclear movement, and the ability of cells to deform their nucleus to invade through confined spaces. Together, our results uncover a role for fascin that operates independently of filopodia assembly to promote efficient cell migration and invasion.

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Section: Resultssupporting

confidence: 94%

Fascin Regulates Nuclear Movement and Deformation in Migrating Cells

et al. 2016

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“…Besides micropillars, polymer scaffolds, and electrospun matrices [25,26,79,80], microfluidic devices made from polydimethylsiloxane (PDMS) by soft lithography [81,82] have proven particularly powerful in investigating cell migration through tight spaces by providing precisely defined microscale structures and constrictions with cross-sections from 100 µm 2 to less than 5 µm 2 [15–21,23,24,64,66,83]. These devices, which often include features to apply stable chemotactic gradients [14–16,18,19,24], allow for user defined geometries ranging from simple straight channels [15,16,24,66] to more intricate designs mimicking physiological environments [18–21,23,83]. The migration devices can be functionalized with a variety of ECM proteins to control cell adhesion.…”

Section: Figurementioning

confidence: 99%

Squish and squeeze — the nucleus as a physical barrier during migration in confined environments

McGregor

Hsia

Lammerding

2016

Current Opinion in Cell Biology

190

152

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From embryonic development to cancer metastasis, cell migration plays a central role in health and disease. It is increasingly becoming apparent that cells migrating in three-dimensional (3-D) environments exhibit some striking differences compared with their well-established 2-D counterparts. One key finding is the significant role the nucleus plays during 3-D migration: when cells move in confined spaces, the cell body and nucleus must deform to squeeze through available spaces, and the deformability of the large and relatively rigid nucleus can become rate-limiting. In this review, we highlight recent findings regarding the role of nuclear mechanics in 3-D migration, including factors that govern nuclear deformability, and emerging mechanisms by which cells apply cytoskeletal forces to the nucleus to facilitate nuclear translocation. Intriguingly, the ‘physical barrier’ imposed by the nucleus also impacts cytoplasmic dynamics that affect cell migration and signaling, and changes in nuclear structure resulting from the mechanical forces acting on the nucleus during 3-D migration could further alter cellular function. These findings have broad relevance to the migration of both normal and cancerous cells inside living tissues, and motivate further research into the molecular details by which cells move their nuclei, as well as the consequences of the mechanical stress on the nucleus.

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“…Cancer cells were shown to migrate through constrictions as narrow as 2 μm formed by PDMS pillars 54 , but nuclear translocation was greatly impeded when the sub-nuclear channel (2-20 μm × 5 μm) was narrower than 5 μm (Ref. 55). These studies advanced the understanding of the morphological changes of cancer cells when they invade spaces with subnuclear confinements.…”

Section: Microfluidic Investigation Of Mechanical Factors In Cancer Cmentioning

confidence: 93%

“…Because the smallest space that cancer cells experience during metastasis can reach sub-nuclear levels 50 and nuclear deformation might lead to downstream mechanotransduction pathways 51 , several devices sufficiently small to confine the cancer cell nucleus were constructed to observe nuclear deformation 43,[52][53][54][55] . These devices demonstrated the protrusion of cancer cell cytoplasm into the sub-nuclear channels prior to nuclear deformation 43,52 .…”

Section: Microfluidic Investigation Of Mechanical Factors In Cancer Cmentioning

confidence: 99%

A review of microfluidic approaches for investigating cancer extravasation during metastasis

et al. 2018

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Metastases, or migration of cancers, are common and severe cancer complications. Although the 5-year survival rates of primary tumors have greatly improved, those of metastasis remain below 30%, highlighting the importance of investigating specific mechanisms and therapeutic approaches for metastasis. Microfluidic devices have emerged as a powerful platform for drug target identification and drug response screening and allow incorporation of complex interactions in the metastatic microenvironment as well as manipulation of individual factors. In this work, we review microfluidic devices that have been developed to study cancer cell migration and extravasation in response to mechanical (section 'Microfluidic investigation of mechanical factors in cancer cell migration'), biochemical (section 'Microfluidic investigation of biochemical signals in cancer cell invasion'), and cellular (section 'Microfluidic metastasis-on-a-chip models for investigation of cancer extravasation') signals. We highlight the device characteristics, discuss the discoveries enabled by these devices, and offer perspectives on future directions for microfluidic investigations of cancer metastasis, with the ultimate aim of identifying the essential factors for a 'metastasis-on-a-chip' platform to pursue more efficacious treatment approaches for cancer metastasis.

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An open access microfluidic device for the study of the physical limits of cancer cell deformation during migration in confined environments

Abstract: Graphical abstract

Cited by 28 publications

References 9 publications

Fascin Regulates Nuclear Movement and Deformation in Migrating Cells

Fascin Regulates Nuclear Movement and Deformation in Migrating Cells

Squish and squeeze — the nucleus as a physical barrier during migration in confined environments

A review of microfluidic approaches for investigating cancer extravasation during metastasis

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