Decreased cell stiffness facilitates detachment and migration of breast cancer cells in 3D collagen matrices: An exploratory study

Tumour-cell detachment is a critical early event in the metastatic cascade. Although several mechanisms have been reported, the role of cell mechanical properties in facilitating cell detachment and migration is not well understood. This exploratory study aimed to assess how intracellular stiffness changes these processes. MDA-MB-231 cells were embedded as 10,000-cell spheroids in 2 and 4 mg/ml collagen matrices. Using mitochondrial-based particle tracking microrheology, the intracellular stiffness was assessed of cells that migrated distances equivalent to four and six times the cell diameter (dC) from the spheroid and compared to cells at the spheroid surface (0dC), representing medium, high and no migration, respectively. The mitochondrial mean square displacement (MSD) and intracellular stiffness decreased during detachment and migration for both collagen concentrations (i.e. rigidities). The MSD of 4dC and 6dC cells was similar, whereas cell stiffness was lower for 4dC than for 6dC cells. The stiffness of 0dC cells decreased with increasing matrix rigidity, whereas matrix rigidity did not affect the stiffness of 4dC and 6dC cells. It is proposed that decreased cell stiffness drives cellular detachment and migration and increased matrix rigidity physically hinders migration where cells need to either decrease their stiffness or remodel the environment to migrate. The absence of an influence of matrix rigidity on the stiffness of migrated cells suggests that cells facilitate migration by remodelling their environment through the cleavage of matrix proteins. Proposed targets for further mechanobiological studies of metastatic cancer cells include the expression of matrix metalloproteinases and transforming growth factor β, and the role of cell volume on detachment and migration in matrices with varying pore sizes.