Current knowledge understands the mesenchymal cell invasion in a 3D matrix as a combined process of cell-to-matrix adhesion based cell migration and matrix remodeling. Excluding cell invasion stimulated by cytokines and chemokines, the basal cell invasion itself is a complicated process that can be regulated by matrix ligand type, density, geometry, and stiffness, etc. Understanding such a complicated biological process requires delicate dissections into simplified model studies by altering only one or two elements at a time. Past cell motility studies focusing on matrix stiffness have revealed that a stiffer matrix promotes 2D X-Y axis lateral cell motility. Here, we comment on two recent studies that report, instead of stiffer matrix, a softer matrix promotes matrix proteolysis and the formation of invadosome-like protrusions (ILPs) along the 3D Z axis. These studies also reveal that soft matrix precisely regulates such ILPs formation in the stiffness scale range of 0.1 kilopascal in normal cells. In contrast, malignant cells such as cancer cells can form ILPs in response to a much wider range of matrix stiffness. Further, different cancer cells respond to their own favorable range of matrix stiffness to spontaneously form ILPs. Thus, we hereby propose the idea of utilizing the matrix stiffness to precisely regulate ILP formation as a mechanophenotyping tool for cancer metastasis prediction and pathological diagnosis.
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