Data driven and biophysical insights into the regulation of trafficking vesicles by extracellular matrix stiffness

Biomechanical signals from remodeled extracellular matrix (ECM) promote tumor progression. Here, we show that cell-matrix and cell-cell communication may be inherently linked and tuned through mechanisms of mechanosensitive biogenesis of trafficking vesicles. Pan-cancer analysis of cancer cells' mechanical properties (focusing primarily on cell stiffness) on substrates of varied stiffness and composition elucidated a heterogeneous cellular response to mechanical stimuli. Through machine learning, we identified a fingerprint of cytoskeleton-related proteins that accurately characterize cell stiffness in different ECM conditions. Expression of their respective genes correlates with patient prognosis across different tumor types. The levels of selected cytoskeleton proteins indicated that cortical tension mirrors the increase (or decrease) in cell stiffness with a change in ECM stiffness. A mechanistic biophysical model shows that the tendency for curvature generation by curvature-inducing proteins has an ultrasensitive dependence on cortical tension. This study thus highlights the effect of ECM stiffness, mediated by cortical tension, in modulating vesicle biogenesis.

Automated summary

Biomechanical signals from remodeled extracellular matrix (ECM) promote tumor progression. Cellular communication and interaction between cell-matrix and cell-cell may be influenced by mechanosensitive biogenesis of trafficking vesicles. Through machine learning, a fingerprint of cytoskeleton-related proteins has been identified to accurately characterize cell stiffness in different ECM conditions. The expression of these genes is correlated with patient prognosis across different tumor types. Cortical tension mirrors the changes in cell stiffness with a change in ECM stiffness. A mechanistic biophysical model shows that curvature generation is highly dependent on cortical tension. This study highlights the effect of ECM stiffness, mediated by cortical tension, in modulating vesicle biogenesis.