Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Tuesday Speaker Abstracts

Mechanobiology of Epithelial-to-Mesenchymal Transition in Confined Environments Amit Pathak . Washington University in St. Louis, St. Louis, MO, USA. Epithelial cells disengage from their clusters and become motile by undergoing epithelial-to- mesenchymal transition (EMT), an essential process for fibrosis and tumor metastasis. Growing evidence suggests that high extracellular matrix (ECM) stiffness induces EMT. However, very little is known about how various geometrical parameters of the ECM might influence EMT. We have adapted a hydrogel-microchannels based matrix platform to culture epithelial clusters in ECMs of tunable stiffness and confinement. We report that epithelial clusters undergo EMT to a greater degree in more confined ECM settings. Surprisingly, cell clusters residing in soft ECMs exploit this confinement-sensitive EMT better than those in stiff ECMs. Upon pharmacological inhibition of microtubules, cells lose the ability to polarize their cytoskeleton in response to ECM confinement, which in turn disables the confinement-sensitive EMT. Disruption of cell- ECM adhesions blunts the influence of ECM stiffness on EMT. To gain quantitative insights into relative contributions of subcellular and extracellular features to the ECM-dependent EMT, we simulated our experimental findings through a novel computational model that combines mechanics-based cellular features into a multi-cell network under varied ECM properties. Our model is based on cooperative operation of cell-ECM adhesions, protrusion dynamics, and actomyosin forces, which collectively dictate the state of cell-cell junctions in each cell of a given epithelial cluster. The model also accounts for the stiffness and the geometry of the ECM surrounding the mutli-cell network. Taken together, our experimental and computational results reveal that ECM confinement alone can induce EMT, even in soft tissue contexts that otherwise maintain epithelial integrity in unconfined environments. These findings highlight that topographical structure and mechanical stiffness of the tissue microenvironment can both independently regulate EMT, which brings a fresh perspective to the current understanding of microenvironment-dependent dissemination and invasion of cancer cells through confined spaces around tumor.

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