Mechanical Interaction of Metastatic Cancer Cells with a Soft Gel

Abstract

The process of invasion is of special importance in cancer metastasis, the main cause of death in cancer patients. Cells typically penetrate a matrix by degrading it or by squeezing through pores. However, cell mechanics and forces applied by cells especially during the initial stages of metastatic penetration, as metastatic cells indent a substrate, are still unknown. Highly metastatic (high MP) breast-cancer cells are internally and externally softer than low MP and benign cells, as a result of cytoskeleton structure and intracellular activity. Although the high MP cells are softer they are still able to apply strong forces. It is the combination of enhanced pliability and strength of these cells contributes to their invasive capabilities. We show that metastatic breast-cancer cells indent, in likely attempted penetration even a non-degradable substrate with sub-micron pores, impenetrable to the cells. We visualize indentation through focal depth changes of particles embedded in the impenetrable substrate. Cells develop grip handles and pull the underlying gels inwards and upwards and then push the cell body into the indentation concavity. Cells repeatedly attempt penetration this way over several hours, and can relocate when penetration is unsuccessful, indicating an advanced mechano-transduction feedback loop. More attempts and stronger forces are applied to stiffer gels and by the low and high MP cells, surprisingly also resulting in deeper indentations by some of the cells on the stiffer gels. Hence, a single, metastatic cell requires substrates to be soft enough to indent, yet stiff enough to generate force on. Our system reveals cell adaptation, force application mechanisms, and can potentially serve as a diagnostic and treatment testing platform.