Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential

Coughlin, Mark F.; Bielenberg, Diane R.; Lenormand, Guillaume; Marinković, Marina; Waghorne, Carol; Zetter, Bruce R.; Fredberg, Jeffrey J.

doi:10.1007/s10585-012-9531-z

Cited by 114 publications

(92 citation statements)

References 74 publications

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“…In contrast, analysis of cells in suspension or nonspread cells would be expected to mainly detect stiffness of the cortical cytoskeletal network and the cell nucleus. In agreement with this, previous reports have indicated that cell spreading is a main determinant of the cell stiffness that is detected (45).…”

Section: Discussionsupporting

confidence: 91%

Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness

Rathje

Nordgren

Pettersson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

101

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Oncogenes deregulate fundamental cellular functions, which can lead to development of tumors, tumor-cell invasion, and metastasis. As the mechanical properties of cells govern cell motility, we hypothesized that oncogenes promote cell invasion by inducing cytoskeletal changes that increase cellular stiffness. We show that the oncogenes simian virus 40 large T antigen, c-Myc, and cyclin E induce spatial reorganization of the vimentin intermediate filament network in cells. At the cellular level, this reorganization manifests as increased width of vimentin fibers and the collapse of the vimentin network. At nanoscale resolution, the organization of vimentin fibers in these oncogene-expressing cells was more entangled, with increased width of the fibers compared with control cells. Expression of these oncogenes also resulted in upregulation of the tubulin deacetylase histone deacetylase 6 (HDAC6) and altered spatial distribution of acetylated microtubules. This oncogene expression also induced increases in cellular stiffness and promoted the invasive capacity of the cells. Importantly, HDAC6 was required and sufficient for the structural collapse of the vimentin filament network, and was required for increased cellular stiffness of the oncogene-expressing cells. Taken together, these data are consistent with the possibility that oncogenes can induce cellular stiffness via an HDAC6-induced reorganization of the vimentin intermediate filament network.colloidal probe force-mode atomic force microscopy | STED microscopy | cell mechanics | cytoskeleton | cell invasion O ncogenes induce major changes in cell behavior that can result in the development of tumors and tumor-cell metastases. Although expression of oncogenes promotes the ability of cells to invade the surrounding environment and to form metastases (1-3), the mechanisms behind this remain to be further elucidated. Many tumors show increased tissue stiffness, which can at least in part be explained by an increase in the stiffness of the extracellular microenvironment in tumors (4). Nonetheless, this increase in stiffness might also be due to an increase in the intrinsic stiffness of the cytoplasm of transformed cells. As the mechanical properties of cells govern their motile behavior, we hypothesized that oncogenes promote cell invasion via the control of cellular stiffness.The cell cytoskeleton is composed of actin filaments, microtubules, and intermediate filaments (IFs), and it is believed to govern the mechanical properties of cells. In particular, the actin filaments have been shown to control cell mechanics (5, 6). In addition, there are a number of observations that indicate that vimentin IFs also contribute to the mechanical properties of cells. Vimentin IFs are a major cytoskeletal component in motile mesenchymal cells and metastatic tumors of epithelial origin. Epithelial-to-mesenchymal transition (EMT) is a diagnostic marker of migration and invasion of cancer cells, and it is characterized by expression of vimentin. Vimentin IFs functionally control...

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Section: Discussionsupporting

confidence: 91%

Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness

Rathje

Nordgren

Pettersson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

101

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“…The mechanical properties of cells are closely related to a number of biological functions, such as cell differentiation, aging, motility, metastasis, and mechanotransduction [1–4]. Several studies have recently suggested that cellular properties can be utilized as label-free biomarkers for disease diagnosis [5–7].…”

Section: Introductionmentioning

confidence: 99%

Characterization of biomechanical properties of cells through dielectrophoresis-based cell stretching and actin cytoskeleton modeling

et al. 2017

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BackgroundCytoskeleton is a highly dynamic network that helps to maintain the rigidity of a cell, and the mechanical properties of a cell are closely related to many cellular functions. This paper presents a new method to probe and characterize cell mechanical properties through dielectrophoresis (DEP)-based cell stretching manipulation and actin cytoskeleton modeling.MethodsLeukemia NB4 cells were used as cell line, and changes in their biological properties were examined after chemotherapy treatment with doxorubicin (DOX). DEP-integrated microfluidic chip was utilized as a low-cost and efficient tool to study the deformability of cells. DEP forces used in cell stretching were first evaluated through computer simulation, and the results were compared with modeling equations and with the results of optical stretching (OT) experiments. Structural parameters were then extracted by fitting the experimental data into the actin cytoskeleton model, and the underlying mechanical properties of the cells were subsequently characterized.ResultsThe DEP forces generated under different voltage inputs were calculated and the results from different approaches demonstrate good approximations to the force estimation. Both DEP and OT stretching experiments confirmed that DOX-treated NB4 cells were stiffer than the untreated cells. The structural parameters extracted from the model and the confocal images indicated significant change in actin network after DOX treatment.ConclusionThe proposed DEP method combined with actin cytoskeleton modeling is a simple engineering tool to characterize the mechanical properties of cells.

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“…Another biomechanical screening approach in the adherent cell is the magnetic twisting cytometry, a commonly used technique to screen for impacts on cell stiffness [92–94]. During magnetic twisting cytometry measurements, ferromagnetic beads (4.5 μm in diameter) are tightly anchored to the cell cytoskeleton and oscillated using a known magnetic field (5–75 Gauss).…”

Section: Selected Bioassays For Use In Mechanopharmacologymentioning

confidence: 99%

Cellular Biomechanics in Drug Screening and Evaluation: Mechanopharmacology

Krishnan

Park

Seow

et al. 2016

Trends in Pharmacological Sciences

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The study of mechanobiology is now widespread. The impact of cell and tissue mechanics on cellular responses is well appreciated. However, knowledge of the impact of cell and tissue mechanics on pharmacological responsiveness, and its application to drug screening and mechanistic investigations, have been very limited in scope. We emphasize the need for a heightened awareness of the important bidirectional influence of drugs and biomechanics in all living systems. We propose that the term ‘mechanopharmacology’ be applied to approaches that employ in vitro systems, biomechanically appropriate to the relevant (patho)physiology, to identify new drugs and drug targets. This article describes the models and techniques that are being developed to transform drug screening and evaluation, ranging from a 2D environment to the dynamic 3D environment of the target expressed in the disease of interest.

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Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential

Cited by 114 publications

References 74 publications

Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness

Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness

Characterization of biomechanical properties of cells through dielectrophoresis-based cell stretching and actin cytoskeleton modeling

Cellular Biomechanics in Drug Screening and Evaluation: Mechanopharmacology

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