Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Thursday Speaker Abstracts

Cancer Cells Sense and Respond to Their Mechanical Environment during Confined Invasion Andrew W. Holle 1 , Kim Clar 1 , Neethu Govindankutty Devi 1,2 , Ralf Kemkemer 1,3 , Joachim P. Spatz 1,4 . 1 Max Planck Institute for Medical Research, Stuttgart, Germany, 2 University of Ulm, Ulm, Germany, 3 Reutlingen University, Reutlingen, Germany, 4 University of Heidelberg, Heidelberg, Germany. Cancer metastasis is dependent upon individual cancer cells to invade through physical tissue barriers when escaping the tumor microenvironment. This process requires traction force generation, mechanotransduction, and subsequent cytoskeletal rearrangement. Two distinct modes of cancer cell invasion, mesenchymal and amoeboid, have been identified, and plasticity of invasion mode can limit the effectiveness of targeted chemotherapy. Microchannels with widths between 3 and 10 μm and lengths over 150 μm were fabricated, necessitating complete movement of the cell into the channel. Nine different cancer cell lines from three different tissue origins were observed interacting with the channels. Of these lines, five were found to successfully permeate from one side of the channel to the other. In four of these lines, migration was faster in narrow 3 μm channels than in wide 10 μm channels. Furthermore, cells navigating narrow channels exhibited blebs and had smooth leading edge profiles, suggesting a transition from mesenchymal invasion to amoeboid invasion. To better understand the role of the cytoskeleton in this process, highly invasive MDA MB-231 breast cancer cells were analyzed individually. Consistent with the hypothesis of a mesenchymal-to-amoeboid transition, a reduction in focal adhesion protein localization was observed in narrow channels, and cells were found to permeate narrow channels even in the absence of cell-binding ECM proteins. Chemical inhibition of the Rho/ROCK and Rac pathways, which underlie amoeboid and mesenchymal invasion respectively, revealed that amoeboid invasion through confined environments may rely on both pathways in a time-dependent manner. SiR-Actin live cell labeling was used to reveal distinct patterns of cytoskeletal organization inside wide and narrow channels. A mechanosensing period was identified in which the cell determines the channel to be too narrow for mesenchymal-based migration, reorganizes its cytoskeleton, and proceeds using an amoeboid phenotype.

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