BIOPHYSICS AND CELL MOTILITY IN CANCER METASTASIS

Abstract

The mechanobiology of cancer dissemination remains to be a topic of interest in the framework of giving better treatment opportunities.  In this paper, the cell motility during metastasizing cancer is investigated with the perspective of quantitative modeling combined with mechanical profiling and imaging-based medical analysis.  Studying the influence of substrate stiffness on the way cells move, we have examined metastatic breast (MDA-MB-231) and pancreatic (PANC-1) cancer cell lines.  Experimental tests confirmed that, by stiffening the extracellular matrix (ECM), cell motility can be increased about 500 times (from 4nm/min to 1.5m/min), the time by which cells will remain in the same location can also be increased significantly (more than 50 minutes), and the force by which cells can move can also be enhanced (up to 120 nN). This indicates how a stiff microenvironment could assist cancer to spread.  Persistent random walk model fits well in the process of cell movement in a specific manner as the parameters of velocity and persistence show strong correlation between replicates.  Manipulating cytoskeletal components using ROCK and microtubule inhibitors decreased traction and elasticity and indicated that actomyosin contractility and microtubule stability were also essential to invasive motility.  Correlation analysis and scatter graphs indicated the direct relationship between the traction force and cellular stiffness. Hybrid visualizations also indicated that velocity and persistence concomitantly rose under the circumstances of cell mechanical stimulation.  These findings were confirmed by transcriptomic analysis identifying that cells grown in high-stiffness matrices had more EMT-related and adhesion-related genes present.  The collective research provides firm indication that cells of metastatic cancer modify their directions of movement and material properties under the influence of mechanical stimuli in the environment.  These findings indicate the extent to which it is necessary to pay attention to the mechanotransduction pathways when designing medicine that would prevent metastasis.  Our experimental system is a system that can be re-used over and over to research the influence of mechanical forces on metastasis. It may be applied in drug screening and precision oncology.