A flexible network of vimentin intermediate filaments promotes migration of amoeboid cancer cells through confined environments

Lavenus, Sandrine; Tudor, Sara M.; Ullo, Maria F; Vosatka, Karl W; Logue, Jeremy S.

doi:10.1074/jbc.ra119.011537

Cited by 46 publications

(53 citation statements)

References 43 publications

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“…This is consistent with the decreased 3D motility rates of cells with VIFs. [66,74,76] On the other hand, cells containing a perinuclear VIF cage seems to serve as a protective structure that increases the effective stiffness of the nuclear envelope, as seen by reduced nuclear deformability in cells expressing vimentin. [74,77] In this way, VIFs not only enhance the cell stiffness but also the effective stiffness of the nuclear envelope.…”

Section: Vimentin Perinuclear Cagementioning

confidence: 99%

“…Recent studies indicate that VIFs also decrease confined cell motility in amoeboid cancer cells. [ 76 ] In dendritic cells vimentin is seen to enhance 3D movement [ 76 ] and provide mechanical resilience to protect the nucleus. [ 77 ] More studies are needed to determine how VIF network assembly and its interactions with the other cytoskeletal components help to establish different modes of confined cell motility.…”

Section: Perinuclear Vimentinmentioning

confidence: 99%

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Mechanical and Non‐Mechanical Functions of Filamentous and Non‐Filamentous Vimentin

et al. 2020

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Intermediate filaments (IFs) formed by vimentin are less understood than their cytoskeletal partners, microtubules and F-actin, but the unique physical properties of IFs, especially their resistance to large deformations, initially suggest a mechanical function. Indeed, vimentin IFs help regulate cell mechanics and contractility, and in crowded 3D environments they protect the nucleus during cell migration. Recently, a multitude of studies, often using genetic or proteomic screenings show that vimentin has many non-mechanical functions within and outside of cells. These include signaling roles in wound healing, lipogenesis, sterol processing, and various functions related to extracellular and cell surface vimentin. Extracellular vimentin is implicated in marking circulating tumor cells, promoting neural repair, and mediating the invasion of host cells by viruses, including SARS-CoV, or bacteria such as Listeria and Streptococcus. These findings underscore the fundamental role of vimentin in not only cell mechanics but also a range of physiological functions. Also see the video abstract here https://youtu.be/ YPfoddqvz-g.

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Section: Vimentin Perinuclear Cagementioning

confidence: 99%

Section: Perinuclear Vimentinmentioning

confidence: 99%

Mechanical and Non‐Mechanical Functions of Filamentous and Non‐Filamentous Vimentin

et al. 2020

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“…This suggests that a stiff nucleus may limit the compressibility of the cell body, reducing leader bleb area. Similarly, we reported that high levels of Vimentin (which is also localized to the cell body) will through the regulation of cell mechanics limit leader bleb area and migration 23 . After confirming our initial hypothesis, which was that nuclear stiffness is important for LBBM, we next set out to determine the precise role of mechanosensitive (Lamin associated) factors in confined (leader bleb-based) migration.…”

Section: Discussionmentioning

confidence: 70%

“…In order to more precisely determine the role of emerin in regulating confined (leader bleb-based) migration, we next turned to a previously described gel sandwich assay for measuring cell stiffnesses 7,23 . Briefly, this assay involves placing cells between two polyacrylamide gels of known stiffness (1 kPa; Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Lavenus

Vosatka

Ullo

et al. 2020

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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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“…Vimentin is an intermediate filament protein that upholds cellular structure and integrity in normal mesenchymal cells. Importantly, during metastasis Vimentin regulates the cell shape and migration ability to support the EMT phenomenon 35 , 36 , 43 . A study demonstrated decreased migration and invasion upon Vimentin knockdown in CRC cells, underlining the significance of Vimentin in regulating EMT 44 , 45 .…”

Section: Discussionmentioning

confidence: 99%

Natural podophyllotoxin analog 4DPG attenuates EMT and colorectal cancer progression via activation of checkpoint kinase 2

et al. 2021

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Epithelial–mesenchymal transition (EMT) is critical for the metastatic dissemination of cancer cells and contributes to drug resistance. In this study, we observed that epithelial colorectal cancer (CRC) cells transiently exposed to 5-fluorouracil (5-FU) (a chemotherapeutic drug for CRC) as well as 5-FU-resistant cells (5-FU-R) develop EMT characters as evidenced by activation of Vimentin and augmented invasive properties. On the other hand, 4DPG (4′-demethyl-deoxypodophyllotoxin glucoside), a natural podophyllotoxin analog attenuates EMT and invadopodia formation abilities of HCT-116/5-FU-R and SW-620/5-FU-R cells. Treatment with 4DPG restrains Vimentin phosphorylation (Ser38) in 5-FU-R cells, along with downregulation of mesenchymal markers Twist1 and MMP-2 while augmenting the expression of epithelial markers E-cadherin and TIMP-1. Moreover, 4DPG boosts the tumor-suppressor protein, checkpoint kinase 2 (Chk2) via phosphorylation at Thr68 in a dose-dependent manner in 5-FU-R cells. Mechanistically, SiRNA-mediated silencing of Chk2, as well as treatment with Chk2-specific small-molecule inhibitor (PV1019), divulges that 4DPG represses Vimentin activation in a Chk2-dependent manner. Furthermore, immunoprecipitation analysis unveiled that 4DPG prevents complex formation between Vimentin and p53 resulting in the rescue of p53 and its nuclear localization in aggressive 5-FU-R cells. In addition, 4DPG confers suitable pharmacokinetic properties and strongly abrogates tumor growth, polyps formation, and lung metastasis in an orthotopic rat colorectal carcinoma model. In conclusion, our findings demonstrate 4DPG as a targeted antitumor/anti-metastatic pharmacological lead compound to circumvent EMT-associated drug resistance and suggest its clinical benefits for the treatment of aggressive cancers.

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A flexible network of vimentin intermediate filaments promotes migration of amoeboid cancer cells through confined environments

Cited by 46 publications

References 43 publications

Mechanical and Non‐Mechanical Functions of Filamentous and Non‐Filamentous Vimentin

Mechanical and Non‐Mechanical Functions of Filamentous and Non‐Filamentous Vimentin

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

Natural podophyllotoxin analog 4DPG attenuates EMT and colorectal cancer progression via activation of checkpoint kinase 2

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