Metastatic cancer cells tenaciously indent impenetrable, soft substrates

Abstract

We present here the first evidence of mechanical penetration by a metastatic cancer cell. During metastasis, the invasive cancer-cell penetrates tissue and extracellular matrix, changes shape and applies force. These applied forces, in turn, depend on substrate stiffness and degradability. The initial stage of metastatic penetration comprises substrate indentation, which, however, has not yet been studied. Hence, we evaluate the evolution of indentation, focusing on differences relating to the metastatic potential (MP) of the cells and substrate stiffness. We found that metastatic cells attain a mushroom-like morphology and then, over several hours, repeatedly indent the substrate in a manner suggestive of a special role for the nucleus. Cells with higher MP have previously been shown to be softer internally and externally than those with lower MP yet, paradoxically, applied stronger forces. Cells of higher MP develop stronger forces on gels stiff enough to provide grip handles yet soft enough to indent, whereas benign cells did not indent substrates at all. These findings provide insight into the central role of physical forces in the initial stages of metastatic penetration and reveal new targets for treatment.

Cytoskeleton and plasma-membrane damage resulting from exposure to sustained deformations: A review of the mechanobiology of chronic wounds

“…Single cells and monolayers have been shown to directly interact with the environment, changing their morphology, applying force and deforming the substrate and neighboring cells [34,35] . Specifically, the Weihs lab have shown that single cancer cells may locally deform soft elastic gels, by modifying their internal structures to facilitate force application [5,36,37] , an ability which correlates directly with their tendency to invade adjacent tissue. Mechanical interactions of cells with their substrates have also been shown to affect differentiation, alignment, and migration capabilities [38][39][40] .…”

Multiple scale model for cell migration in monolayers: Elastic mismatch between cells enhances motility

“…One example is cancer metastasis, where a cancer cell squeezes through the endothelium to reach the blood stream and eventually forms a secondary tumor elsewhere in the body1234. Over recent years, the study of cancer from a physical sciences point of view has drawn much attention35678910: Physical principles are believed to offer an alternative perspective of the disease and may help to optimize treatments11 and detection12. The model we present in this paper emphasizes the role of the elastic properties of cancer cells and surrounding normal cells on the metastatic potential of the former.…”

Measuring cellular traction forces on non-planar substrates

“…A cell is modelled as a circle with traction patches located only in a peripheral annulus of width d. Each of these patches carries a tangential traction stress of f ¼ 3 kPa, which is a typical value found for cells [63,64]. However, previous studies also reported appreciable cellular traction stress in normal directions [39,65,66]. They found a typical pull-push pattern, such that the cell is pulling up at the periphery and pushing down with the cell body.…”