Abstract
Cells adhere to substrates through mechanosensitive focal adhesion complexes. Measurements that probe how cells detach from substrates when they experience an applied force connect molecular-scale aspects of cell adhesion with the biophysical properties of adherent cells. Such forces can be applied through shear devices that flow fluid in a controlled manner across cells. The signaling pathways associated with focal adhesions, in particular those that involve integrins and receptor tyrosine kinases, are complex, receiving mechano-chemical feedback from the sensing of substrate stiffness as well as of external forces. This article reviews the signaling processes involved in mechanosensing and mechanotransduction during cell-substrate interactions, describing the role such signaling plays in cancer metastasis. We examine some recent progress in quantifying the strength of these interactions, describing a novel fluid shear device that allows for the visualization of the cell and its sub-cellular structures under a shear flow. We also summarize related results from a biophysical model for cellular de-adhesion induced by applied forces. Quantifying cell-substrate adhesions under shear should aid in the development of mechano-diagnostic techniques for diseases in which cell-adhesion is mis-regulated, such as cancers.
Highlights
Cells encounter mechanical forces through their contacts with other cells in tissue as well as from flows in the vasculature
We provide a comparison of various methods to quantify cell-substrate adhesions
We have discussed the biological responses of cells subjected to shear stress, biophysical methods to quantify cell-substrate adhesions, and analytical approaches to model these responses
Summary
Cells encounter mechanical forces through their contacts with other cells in tissue as well as from flows in the vasculature. Focal adhesions (FA), key sites of transmembrane integrin clustering, mediate intracellular force transmission through dynamic mechano-sensitive complexes (Hynes, 2002). These complexes are connected, both mechanically and through biochemical signaling pathways, to the cytoskeleton (Baratchi et al, 2017). Nascent adhesions formed by cells on substrates generally undergo maturation or turnover associated with the recruitment and assembly of actin (Oakes et al, 2014) This maturation requires tensional force, mediated through inactivation of focal adhesion kinase (FAK), the phosphorylation of Src and p190RhoGAP to decrease the activity of Rho and Rho kinase (ROCK) in cells, the recruitment of Rac and other protein complexes to the adhesion sites and a decrease in the local myosin contractility (von Wichert et al, 2003; Broussard et al, 2008). They may help in the development of therapeutic agents that target the role of integrins in cancer metastasis
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