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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