Modeling cell trapping and anomalous cell migration on viscoelastic substrates

Introduction:: Cell migration is an essential biological process that plays a key role in immune cell trafficking, embryogenesis, wound healing, and cancer metastasis. Biological tissues are compliant and exhibit viscoelasticity, showing stress relaxation in response to applied deformation. Substrate stress relaxation is emerging as a key mediator for diverse cellular processes such as cell proliferation, spreading, and stem cell differentiation. Cell migration on elastic substrates is frequently described as a purely diffusive, random walk. However, the impact of substrate stress relaxation on diffusive cell migration has not been studied. Here, by combining simulations and experiments, we systematically investigate the effect of substrate stress relaxation on cell migration modes.

Materials and Methods:: Human fibrosarcoma cells HT1080 (ATCC) were used to study their migration properties using confocal microscopy. We utilised an alginate-reconstituted basement membrane (rBM) compliant substrate (~2kPa Young’s modulus) with independently tunable stress relaxation properties. Substrate stress relaxation was modulated by changing alginate molecular weight to obtain characteristic stress relaxation times similar to those observed for biological tissues. We developed a cell migration model based on the motor clutch framework that consists of motors (retrograde flow through actomyosin contractility) and clutches (cell-ECM adhesion). To account for the viscoelasticity of the ECM, a standard linear solid (SLS) model that contains three elements: long-term modulus, additional modulus, and viscosity, is applied. In our model, we account for the heterogeneity in the rate dynamics of adhesion bonds using a power law distribution derived from the kinetic modeling of protein unfolding.

Results, Conclusions, and Discussions:: Quantification of trap time shows that cells have longer trap time on slow-relaxing substrates compared to their fast-relaxing counterparts. This suggests that fast-relaxing substrates can potentiate the transition out of a ‘trapped’ state. The simulations provide additional mechanistic insight into the observed migration modes. The unloaded off-rate is not constant during migration, rather, it is probabilistic in nature. We hypothesize that this is due to the glassiness in the protein unfolding response. Our model shows, for the first time, that heterogeneity in the unbinding dynamics of clutches coupled with substrate viscoelastic properties governs the mode of migration. Lastly, we have experimentally validated our model predictions by perturbating the system with actin and myosin inhibitions and analyzing their effects on migration mode. Thus, cell trapping and anomalous migration governed by substrate stress relaxation facilitate new directions in cancer progression research.

Acknowledgements (Optional): :

References (Optional): :