Mechanical Stiffness Grades Metastatic Potential in Patient Tumor Cells and in Cancer Cell Lines

TLDR

Cancer cells invade through the basement membrane, but the role of their mechanical stiffness in this process remains unclear. The study aimed to determine whether cell stiffness inversely correlates with migration and invasion in patient tumor cells and cancer cell lines. Using a magnetic tweezer system, the authors measured cellular stiffness and assessed its relationship with invasion through three‑dimensional basement membranes, revealing a power‑law correlation. They found that highly migratory and invasive cells are five times less stiff than low‑invasive cells, that pharmacologically reducing stiffness increases invasiveness while restoring stiffness via TβRIII/betaglycan decreases it, establishing a power‑law link that enables rapid mechanical grading of metastatic potential and identifies stiffness‑regulating pathways as therapeutic targets.

Abstract

Cancer cells are defined by their ability to invade through the basement membrane, a critical step during metastasis. While increased secretion of proteases, which facilitates degradation of the basement membrane, and alterations in the cytoskeletal architecture of cancer cells have been previously studied, the contribution of the mechanical properties of cells in invasion is unclear. Here, we applied a magnetic tweezer system to establish that stiffness of patient tumor cells and cancer cell lines inversely correlates with migration and invasion through three-dimensional basement membranes, a correlation known as a power law. We found that cancer cells with the highest migratory and invasive potential are five times less stiff than cells with the lowest migration and invasion potential. Moreover, decreasing cell stiffness by pharmacologic inhibition of myosin II increases invasiveness, whereas increasing cell stiffness by restoring expression of the metastasis suppressor TβRIII/betaglycan decreases invasiveness. These findings are the first demonstration of the power-law relation between the stiffness and the invasiveness of cancer cells and show that mechanical phenotypes can be used to grade the metastatic potential of cell populations with the potential for single cell grading. The measurement of a mechanical phenotype, taking minutes rather than hours needed for invasion assays, is promising as a quantitative diagnostic method and as a discovery tool for therapeutics. By showing that altering stiffness predictably alters invasiveness, our results indicate that pathways regulating these mechanical phenotypes are novel targets for molecular therapy of cancer.