LINC complex-Lis1 interplay controls MT1-MMP matrix digest-on-demand response for confined tumor cell migration

Infante, Elvira; Castagnino, Alessia; Ferrari, Raffaele; Monteiro, Pedro T.; Agüera-González, Sonia; Paul‐Gilloteaux, Perrine; Domingues, Mélanie J.; Maiuri, Paolo; Raab, Matthew; Shanahan, Catherine M.; Baffet, Alexandre D.; Piel, Matthieu; Gomes, Edgar R.; Chavrier, Philippe

doi:10.1038/s41467-018-04865-7

Cited by 100 publications

(113 citation statements)

References 70 publications

(94 reference statements)

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“…In contrast, on wider lines, they occupy a location at the front of the nucleus, as previously reported for mesenchymal cells (Bettinger et al, 2009;Doyle et al, 2009). The functional significance of this polarity switch is still largely unknown, but might be relevant in cancer cells to allow matrix degradation in front of the nucleus (Infante et al, 2018;Kim et al, 2010). Interestingly, migration on thin lines has been shown to promote a motility mode similar to the one observed in 3D microenvironments, indicating that this system could be used as a simplified tool for the study of mechanisms controlling cell migration in more complex microenvironments (Doyle et al, 2009;Karuri et al, 2004;Teixeira et al, 2003).…”

Section: Adhesion-limited Migrationmigration Of Cells Along Patternedsupporting

confidence: 54%

“…Migrating single cells, especially mesenchymal cells like fibroblasts and some tumor cells, can move along thin fibers (Harrison, 1911;Infante et al, 2018) and other tracks in tissues and in reconstituted matrices (Doyle et al, 2009;Elkhatib et al, 2017;Schumann et al, 2010). This phenomenon can be mimicked with minimal systems such as suspended fibers (Guetta-Terrier et al, 2015;Janson and Putnam, 2015) or by using thin printed lines of adhesive molecules on a 2D substrate (Clark and Vignjevic, 2015;Doyle et al, 2009) (see poster).…”

Section: Adhesion-limited Migrationmigration Of Cells Along Patternedmentioning

confidence: 99%

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Reconstitution of cell migration at a glance

García-Arcos

Chabrier

Deygas

et al. 2019

Journal of Cell Science

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Single cells migrate in a myriad of physiological contexts, such as tissue patrolling by immune cells, and during neurogenesis and tissue remodeling, as well as in metastasis, the spread of cancer cells. To understand the basic principles of single-cell migration, a reductionist approach can be taken. This aims to control and deconstruct the complexity of different cellular microenvironments into simpler elementary constrains that can be recombined together. This approach is the cell microenvironment equivalent of in vitro reconstituted systems that combine elementary molecular players to understand cellular functions. In this Cell Science at a Glance article and accompanying poster, we present selected experimental setups that mimic different events that cells undergo during migration in vivo. These include polydimethylsiloxane (PDMS) devices to deform whole cells or organelles, micro patterning, nano-fabricated structures like grooves, and compartmentalized collagen chambers with chemical gradients. We also outline the main contribution of each technique to the understanding of different aspects of single-cell migration.

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Section: Adhesion-limited Migrationmigration Of Cells Along Patternedsupporting

confidence: 54%

Section: Adhesion-limited Migrationmigration Of Cells Along Patternedmentioning

confidence: 99%

Reconstitution of cell migration at a glance

García-Arcos

Chabrier

Deygas

et al. 2019

Journal of Cell Science

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“…Collagen degradation is also a requirement in the DCIS intraductal xenograft tumor model for the transition from in situ-to-invasive carcinoma ( 17,18 ). We thus assessed the collagen degradation activity of DCIS cells embedded into a 3D type I collagen matrix for 12 h and stained with an antibody that specifically recognizes the collagenase-cleaved ¾ fragment of collagen I ( 17,33,34 ). Importantly, cells were treated with drugs, or confined for several hours, and then were embedded in the 3D collagen gel in the absence of any further DNA damaging condition.…”

Section: Resultsmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

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While mutations leading to a fragile envelope of the cell nucleus are well known to cause diseases such as muscular dystrophies or accelerated aging, the pathophysiological consequences of the recently discovered mechanically induced nuclear envelope ruptures in cells harboring no mutation are less known. Here we show that repeated loss of nuclear envelope integrity in nuclei experiencing mechanical constraints promotes senescence in nontransformed cells, and induces an invasive phenotype including increased collagen degradation in human breast cancer cells, both in vitro and in a mouse xenograft model of breast cancer progression. We show that these phenotypic changes are due to the presence of chronic DNA damage and activation of the ATM kinase. In addition, we found that depletion of the cytoplasmic exonuclease TREX1 is sufficient to abolish the DNA damage in mechanically challenged nuclei and to suppress the phenotypes associated with the loss of nuclear envelope integrity. Our results also show that TREX1-dependent DNA damage induced by physical confinement of tumor cells inside the mammary duct drives the progression of in situ breast carcinoma to the invasive stage. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells. Main text:( 16,21-23 ), and corresponds to cells squeezing each other as they move. These deformed nuclei were also more often positive for γH2AX than less deformed ones, and in general displayed more intense γH2AX staining than nuclei in the bulk of the tumor ( Fig. 1A-C). This suggests that, at the in situ stage of human breast carcinoma, strands of motile cells at the periphery of the tumor exhibit pronounced nuclear deformation, associated with elevated DNA damage.We then investigated a xenograft mouse model based on the intraductal (intra-nipple) injection of transformed human breast MCF10DCIS.com (DCIS) cells, which are derived from the nontransformed MCF10A cell line, and that recapitulates the transition from in situ to invasive stages of breast cancer progression ( 17,24 ). Tumors at various stages were analyzed. In situ tumors (further divided in early and advanced stages based on the continuity of the myoepithelial layer) are characterized by a myoepithelial layer (stained with smooth muscle actin) surrounding human xenograft cells that were identified by the human-specific KU70 antibody. In order to verify whether human tumor cells similarly experience DNA damage in the tumor xenografts, tumor sections were stained with γH2AX ( Fig. 1E-F, Fig. S1A). Similar to human tumor specimens, xenograft tumors displayed numerous deformed nuclei, mostly found at the periphery of the tumor mass, close to the myoepithelium, especially in ducts inflated with large tumors (Fig. 1E-F), and enriched in regions showing micro-invasive foci. Strikingly, these regions were also enriched in γH2AX-positive nuclei (Fig. 1F). Since γH2AX is also known...

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“…In addition, lamin A expression, often measured as lamin A:B ratio, positively correlated with ECM rigidity , indicating lamin A as the main structure mediating resistance to deformation force. Accordingly, migrating rates of nontransformed fibroblasts and invasive cancer cells in confining substrates in vitro, such as collagen, PDMS channels or transwell chambers, depend on the expression level of lamin A/C (Davidson et al, 2014;Greiner et al, 2014;Harada et al, 2014;Infante et al, 2018;Lautscham et al, 2015;Ribeiro et al, 2014;Rowat et al, 2013;Shin et al, 2013;Yadav et al, 2018), in line with findings that softer tumor cells associate with higher invasion rates (Swaminathan et al, 2011). With cancer progression, the de-differentiation of tumor cells and acquisition of stem cell properties is often accompanied by de-regulated A-as well as B-type lamin expression (Alhudiri et al, 2019;Broers J.L.V., 2014;Chow et al, 2012;Denais and Lammerding, 2014;Saarinen et al, 2015;Wazir et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Lamin B2 follows lamin A/C- mediated nuclear mechanics and cancer cell invasion efficacy

Vortmeyer-Krause

Lindert

Riet

et al. 2020

Preprint

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2Abbreviations: 2D, two-dimensional; 3D, three-dimensional; AFS, atomic force spectroscopy; ECM, extracellular matrix; H2B, histone-2B; MMP matrix metalloproteinase; NII, nuclear irregularity index; NT, non-targeting control; PDMS, polydimethylsiloxane SummaryNuclear deformability during cancer cell invasion and metastasis is critically regulated by lamin A. Here, researchers showed that lamin B2 also contributes to nuclear mechanics, implicating cooperating lamin networks regulating nuclear integrity, migration efficacy, and metastatic tumor progression. AbstractInterstitial tumor cell invasion depends upon complex mechanochemical adaptation of both cell body and the rigid nucleus in response to extracellular tissue topologies. Nuclear mechanics during cell migration through confined environments is controlled by A-type lamins, however, the contribution of B-type lamins to the deformability of the nucleus remains unclear. Using systematic expression regulation of different lamin isoforms, we applied multi-parameter wet-lab and in silico analysis to test their impact on nuclear mechanics, shape regulation, and cancer cell migration. Modulation of lamin A/C and B2 but not B1 isoforms controlled nuclear deformation and viscoelasticity, whereby lamin B2 generally followed lamin A/C-mediated effects. Cell migration rates were altered by 5 to 9fold in dense collagen environments and synthetic devices, with accelerated rates after lamin downregulation and reverse effects after lamin upregulation, with migration rates strongly depending on nuclear shape change. These findings implicate cooperation of lamin B2 with lamin A/C in regulating nuclear mechanics for shape adaptation and migration efficacy.

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LINC complex-Lis1 interplay controls MT1-MMP matrix digest-on-demand response for confined tumor cell migration

Cited by 100 publications

References 70 publications

Reconstitution of cell migration at a glance

Reconstitution of cell migration at a glance

Compromised nuclear envelope integrity drives tumor cell invasion

Lamin B2 follows lamin A/C- mediated nuclear mechanics and cancer cell invasion efficacy

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