The nucleus acts as a ruler tailoring cell responses to spatial constraints

Lomakin, Alexis J.; Cattin, Cédric J.; Cuvelier, Damien; Alraies, Zahraa; Molina, Maria P.; Nader, Guilherme P.F.; Srivastava, Nishit; García-Arcos, Juan Manuel; Zhitnyak, Irina Y.; Bhargava, Anvita; Driscoll, Meghan; Welf, Erik S.; Fiolka, Reto; Petrie, Ryan J.; Manel, Nicolas; Lennon-Duménil, Ana-María; Müller, Daniel J.; Piel, Matthieu

doi:10.1101/863514

Cited by 26 publications

(41 citation statements)

References 42 publications

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“…Here we propose that tumor growth associated with the formation of peripheral motile strands of cells leads to strong deformation of the nucleus at the tumor edges. Nuclear deformation has been associated with several pathways ( 53 ), either triggering immediate cellular response, for example leading to an increase in cell contractility and motility ( 54,55 ), or to longer term responses associated with changes in gene expression and overall cell state or fate ( 56 ). Nuclear deformation was also shown to trigger YAP entry into the nucleus ( 57 ), and to trigger G1/S transition ( 58 ), thus potentially favoring cell proliferation.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

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“…In contrast to the better known mechanisms of mechanotransduction in adherent cells (which often involve Src), cells may use different mechanisms for sensing confinement 31 . This idea is supported by recent evidence that the INM unfolds and activates a cytosolic Phospholipase A2 (cPLA2)-dependent mechanotransduction pathway in confined cells, increasing actomyosin contractility 12,13 .…”

Section: Discussionmentioning

confidence: 75%

“…Furthermore, this phenotypic transition has been found to be promoted by cell confinement 7,8,10,11 . Although compressing the cell (i.e., confinement) may be sufficient to pressurize the cytoplasm, recent studies have suggested that cells adapt to confinement by upregulating actomyosin contractility 12,13 . Because of this dependence on confinement, rapid LBBM is likely to require the precise tuning of cell stiffness.…”

Section: Introductionmentioning

confidence: 99%

Emerin regulation of nuclear stiffness is required for fast amoeboid migration in confined environments

Lavenus

Vosatka

Ullo

et al. 2020

Preprint

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AbstractThrough the process of regulating cell deformability in confined environments, the nucleus has emerged as a major regulator of cell migration. Here, we demonstrate that nuclear stiffness regulates the confined (leader bleb-based) migration of cancer cells. Using high-resolution imaging, we demonstrate that modifying the level of the Inner Nuclear Membrane (INM) protein, emerin, will inhibit Leader Bleb-Based Migration (LBBM). In line with the notion that nuclear stiffness regulates LBBM, stiffness measurements indicate that nuclei are softest at endogenous levels of emerin. Emerin has been found to be phosphorylated by Src in response to force, increasing nuclear stiffness. Accordingly, we found LBBM to be insensitive to increasing levels of emerin (Y74F/Y95F). Using a biosensor, Src activity is found to negatively correlate with cell confinement. Thus, our data are consistent with a model in which low Src activity maintains a soft nucleus and promotes the confined (leader bleb-based) migration of cancer cells.

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“…Opisthokont ancestors might have crawled using a combination of blebs (as in amoeboid choanoflagellates, amoeboid animal cells 9,11 , and amoebozoans 44 ), pseudopods (which are present in choanoflagellates during phagocytosis 22,39 and during crawling in chytrid fungi 8,39 , amoebozoans 44 , and some holozoans 38 ), and filopodia (which contribute to locomotion in filastereans 63 and choanoflagellate settlement 30 ). Moreover, cell crawling is regulated by confinement in animal cells 9–12 , choanoflagellates, chytrid fungi 39 and dictyostelid amoebozoans 44 , suggesting that the ability to respond to confinement might be an ancient feature. These prior findings, together with our observation of an amoeboid switch in choanoflagellates, suggest that the switch from a flagellate to a crawling phenotype in response to confinement was part of an ancestral stress response in the last common choanozoan ancestor 74 .…”

mentioning

confidence: 99%

“…4p). However, the ancient response to confinement was not necessarily fully lost – as confinement activates blebbing in vertebrate mesenchymal and embryonic cells 9,11 through a transduction pathway that makes use of newly evolved proteins, such as the phospholipase cPLA2 10,12 that does not exist in choanoflagellates 21,75 .…”

mentioning

confidence: 99%

A flagellate-to-amoeboid switch in the closest living relatives of animals

Brunet

Albert

Roman

et al. 2020

Preprint

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The evolution of different cell types was a key process of early animal evolution1–3. Two fundamental cell types, epithelial cells and amoeboid cells, are broadly distributed across the animal tree of life4,5 but their origin and early evolution are unclear. Epithelial cells are polarized, have a fixed shape and often bear an apical cilium and microvilli. These features are shared with choanoflagellates – the closest living relatives of animals – and are thought to have been inherited from their last common ancestor with animals1,6,7. The deformable amoeboid cells of animals, on the other hand, seem strikingly different from choanoflagellates and instead evoke more distantly related eukaryotes, such as diverse amoebae – but it has been unclear whether that similarity reflects common ancestry or convergence8. Here, we show that choanoflagellates subjected to spatial confinement differentiate into an amoeboid phenotype by retracting their flagella and microvilli, generating blebs, and activating myosin-based motility. Choanoflagellate cell crawling is polarized by geometrical features of the substrate and allows escape from confined microenvironments. The confinement-induced amoeboid switch is conserved across diverse choanoflagellate species and greatly expands the known phenotypic repertoire of choanoflagellates. The broad phylogenetic distribution of the amoeboid cell phenotype across animals9–14 and choanoflagellates, as well as the conserved role of myosin, suggests that myosin-mediated amoeboid motility was present in the life history of their last common ancestor. Thus, the duality between animal epithelial and crawling cells might have evolved from a temporal phenotypic switch between flagellate and amoeboid forms in their single-celled ancestors3,15,16.

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The nucleus acts as a ruler tailoring cell responses to spatial constraints

Cited by 26 publications

References 42 publications

Compromised nuclear envelope integrity drives tumor cell invasion

Compromised nuclear envelope integrity drives tumor cell invasion

Emerin regulation of nuclear stiffness is required for fast amoeboid migration in confined environments

A flagellate-to-amoeboid switch in the closest living relatives of animals

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