Biology subjects

Iwamoto, D.

Publications and source records attributed to Iwamoto, D..

3 recordsLinked to original sources

bioRxiv2025

Tissue-dependent mechanosensing by cells derived from human tumors

Alterations of the extracellular matrix (ECM), including both mechanical (such as stiffening of the ECM) and chemical (such as variation of adhesion proteins and deposition of hyaluronic acid (HA)) changes, in malignant tissues have been shown to mediate tumor progression. To survey how cells from different tissue types respond to various changes in ECM mechanics and composition, we measured physical characteristics (adherent area, shape, cell stiffness, and cell speed) of 25 cancer and 5 non-tumorigenic cell lines on 7 different substrate conditions. Our results indicate substantial heterogeneity in how cell mechanics changes within and across tissue types in response to mechanosensitive and chemosensitive changes in ECM. The analysis also underscores the role of HA in ECM with some cell lines showing changes in cell mechanics in response to presence of HA in soft substrate that are similar to those observed on stiff substrate. This pan-cancer investigation also highlights the importance of tissue-type and cell line specificity for inferences made based on comparison between physical properties of cancer and normal cells. Lastly, using unsupervised machine learning, we identify phenotypic classes that characterize the physical plasticity, i.e. the distribution of physical feature values attainable, of a particular cell type in response to different ECM-based conditions.

biophysics↗

bioRxiv2022

Extracellular vimentin is sufficient to promote cell attachment, spreading, and motility by a mechanism involving N-acetyl glucosamine-containing structures

Vimentin intermediate filaments form part of the cytoskeleton of mesenchymal cells, but under pathological conditions often associated with inflammation, vimentin filaments depolymerize as the result of phosphorylation or citrullination, and vimentin oligomers are secreted or released into the extracellular environment. In the extracellular space, vimentin can bind surfaces of other cells and the extracellular matrix, and the interaction between extracellular vimentin and other cell types can trigger changes in cellular functions, such as activation of fibroblasts to a fibrotic phenotype. The mechanism by which extracellular vimentin binds external cell membranes and whether vimentin alone can act as an adhesive anchor for cells is largely uncharacterized. Here, we show that various cell types (normal and vimentin null fibroblasts, mesenchymal stem cells, A549 lung carcinoma cells) attach to and spread on polyacrylamide hydrogel substrates covalently linked to vimentin. Using traction force microscopy and spheroid expansion assays, we characterize how different cell types respond to extracellular vimentin. Cell attachment to and spreading on vimentin-coated surfaces is inhibited by hyaluronic acid (HA) degrading enzymes, HA synthase inhibitors, soluble heparin, or N-acetyl glucosamine, treatments that have little or no effect on the same cell types binding to collagen-coated hydrogels. These studies highlight the effectiveness of substrate-bound vimentin as a ligand for cells and suggest that carbohydrate structures, including the glycocalyx and glycosylated cell surface proteins that contain N-acetyl glucosamine, form a novel class of adhesion receptors for extracellular vimentin.

biophysics↗

bioRxiv2017

New Insights into the Conformational Activation of Full-Length Integrin

Integrin binding to extracellular matrix proteins is regulated by conformational transitions from closed, low affinity states to open, high affinity states. However, the pathways of integrin conformational activation remain incompletely understood. Here, by combining all-atom molecular dynamics simulation, coarse-graining, heterogeneous elastic network modeling, and experimental ligand binding measurements, we test the effect of integrin {beta} mutations that destabilize the closed conformation. Our results support a \"deadbolt\" model of integrin activation, where extension of the headpiece is not coupled to leg separation, consistent with recent cryo-EM reconstructions of integrin intermediates. Moreover, our results are inconsistent with a \"switchblade-like\" mechanism. The data show that locally correlated atomistic motions are likely responsible for extension of integrin headpiece before separation of transmembrane legs, without persistence of these correlations across the entire protein. By combining modeling and simulation with experiment, this study provides new insight into the structural basis of full-length integrin activation.

biophysics↗