Multiscale modeling of cell‒substrate adhesion dynamics: effects of integrin activation, clustering and internalization

Cell adhesion is a fundamental biological process that governs cell proliferation, differentiation, migration, and tissue development. Cells adhere to the extracellular matrix through specialized transmembrane proteins, whose structures and functions are well studied. However, how mechanical, chemical, and biological factors interact to regulate these proteins and hence to shape cross-scale adhesion dynamics from molecular clustering to cellular migration remains unclear. Here, we propose a multiscale mechano-biochemical coupling framework to investigate the dynamics of cell‒substrate adhesions, incorporating comprehensive molecular steps in the integrin life cycle, including activation, clustering, signal transduction and internalization. Our model elucidates the roles of caveolin transport and actin flow in modulating integrin dynamics and FA morphology. We identify the antagonistic interplay between integrin internalization and clustering that governs cross-scale adhesion dynamics. Furthermore, our model quantitatively demonstrates how the substrate stiffness regulates the integrin clustering size and internalization rate. These findings provide mechanistic insights into the regulation of cell migration, particularly the transition between durotaxis and negative durotaxis, driven by intracellular and extracellular microenvironmental factors. Our model offers an effective framework for understanding the cross-scale regulation process of cell adhesion involved in physiological and pathological activities, such as stem cell differentiation and cancer metastasis.