Proximity of Metastatic Cells Strengthens the Mechanical Interaction with Their Environment

Abstract

The main cause of cancer-related deaths is metastasis-spreading of cancer cells to different sites in the body. A critical step in metastasis formation is invasion of cells through the surrounding tissue. During invasion, cancer cells change their shape and apply forces. We have previously identified that about 30% of single, metastatic, breast cancer cells will indent impenetrable synthetic, non-degradable, polyacrylamide gels, when gel stiffness is in the range 1–10 kPa. By measuring the depth of indentation of an initially flat gel and monitoring time-dependent microscopic changes in cell morphology, we were able to distinguish between benign and metastatic cells, also identifying their metastatic potential (MP); benign cells do not indent the gels. Recent works have indicated that metastases from solid tumors occur predominantly by collective cell invasion. Hence, in the current study we evaluate the mechanical interactions of cell clusters with the impenetrable gel. We observe that indenting subpopulations of metastatic cells are doubled in clusters, and cells are also indent more deeply; this increases likelihood to successfully form metastasis in the body. Concurrently, double the fraction of high MP cells indent gels as compared to low MP cells, while benign cells do not indent even in clusters. We also show that the gel platform can be used to determine the time-dependent impact of chemotherapeutics on the cells’ ability to apply forces and indent gels. Our approach can provide a rapid, mechanical prediction of the likelihood for invasiveness of cancer cells and can further be applied in a patient-specific approach, thus providing a personalized prognosis that may improve treatment of cancer patients and increase their life expectancy.