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Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Coating Technology.
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Fibre Technology.ORCID iD: 0000-0002-5444-7276
KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
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2014 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 4, 1515-1520 p.Article in journal (Refereed) Published
Abstract [en]

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 up-regulation 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.

Place, publisher, year, edition, pages
2014. Vol. 111, no 4, 1515-1520 p.
Keyword [en]
STED microscopy, cell invasion, cell mechanics, colloidal probe force-mode atomic force microscopy, cytoskeleton
National Category
Biological Sciences
URN: urn:nbn:se:kth:diva-141113DOI: 10.1073/pnas.1300238111ISI: 000330231100069PubMedID: 24474778ScopusID: 2-s2.0-84893371702OAI: diva2:694708

QC 20140207

Available from: 2014-02-07 Created: 2014-02-07 Last updated: 2014-02-27Bibliographically approved
In thesis
1. Super resolution optical imaging – image analysis, multicolor development and biological applications
Open this publication in new window or tab >>Super resolution optical imaging – image analysis, multicolor development and biological applications
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on super resolution STED optical imaging. STED provides a wealth of new informational content to the acquired images by using stimulated emission to surpass the diffraction limit in optical fluorescence microscopy. To further increase the informational content, a new method to perform multicolor STED imaging by exploiting differences in the photostability and excitation spectra of dyes is presented. In order to extract information from the images, computational algorithms which handle the new type of high resolution informational content are developed.

We propose that multicolor super resolution imaging in combination with image analysis can reduce the amount of clinical samples required to perform accurate cancer diagnosis. To date, such diagnosis is based mainly on significant amounts of tissue samples extracted from the suspected tumor site. The sample extraction often requires anesthetics and can lead to complications such as hematoma, infections and even cancer cell ceding along the needle track. We show that by applying multicolor STED and image analysis, the information gained from single cells is greatly increased. We therefore propose that accurate diagnosis can be based on significantly less extracted tissue material, allowing for a more patient friendly sampling. This approach can also be applied when studying blood platelets, where we show how the high informational content can be used to identify platelet specific activational states. Since platelets are involved in many different types of diseases, such analysis could provide means of performing truly minimally invasive diagnostics based on a simple blood test.

In addition, our data makes it possible to understand in finer detail the underlying mechanisms rendering cells metastasis competent. We combine the high resolution spatial information provided by STED with information regarding the adhesive forces of cells measured by TFM (Traction Force Microscopy) and the cell stiffness measured by AFM (Atomic Force Microscopy). Such comparisons provide a link between the specific highly resolved protein distributions and different cellular mechanics and functions.

This thesis also includes STED imaging and analysis on the spatial organization of neuronal synaptic regulating proteins, implicating the speed with which neuronal signaling can be regulated.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2014. x, 86 p.
TRITA-FYS, ISSN 0280-316X ; 2014:04
Stimulated emission depletion (STED) microscopy, nanoscopy, multicolor, image analysis, diagnostics, cancer, metastasis
National Category
Physical Sciences
Research subject
Biological Physics
urn:nbn:se:kth:diva-141011 (URN)978-91-7595-001-3 (ISBN)
Public defence
2014-02-28, FB42, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:51 (English)

QC 20140207

Available from: 2014-02-07 Created: 2014-02-05 Last updated: 2014-02-07Bibliographically approved

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