Characterization of integrin tension during chemotaxis of metastatic cancer cells in confinement.

Abstract

Chemotactic migration plays a critical role in cancer propagation and metastasis. It has been identified that the adhesion strength and degree of physical constraint govern the changes in cell migration from mesenchymal to amoeboid migrations when the cells permeate micron-scale gaps. During the transition, it is presumed that the physical interactions between integrins activated by mechanical tension and ligands in the microenvironment are deeply associated, from adhesion up to migration. However, despite the importance of the physical interplay between the integrins and ligands in the tumor microenvironment, quantitative analysis of the integrin tension during cancer migration in the microenvironment remains incomplete owing to the lack of appropriate measurement tools. Here, we report a new platform termed microconfinement tension gauge tether (µC-TGT). The TGT, a mechanically rupturable DNA-based single-molecule force sensor, is originally designed to measure how the peak integrin tension influenced cell behavior and the amount of integrin tension experienced or exerted by the cells. Using a combination of TGT assay and microfluidics, we monitored the spatial integrin tension by analyzing the epithelial growth factor (EGF)-induced chemotaxis of human breast cancer cells in microchannels. We thus demonstrate that the metastatic cancer cells exert the strongest integrin tension in the range of 54 to 100 pN at the cell edges during chemokinetic migration on a planar surface, whereas the cells entering the microchannels exert the strongest integrin tension exceeding 100 pN at the cell rear. Next, we observed the cells undergo mesenchymal migration under high integrin tension and less confinement, which is converted to amoeboid migration under low integrin tension or high confinement, thereby allowing us to identify a basic mechanism underlying the mechanical interactions between integrin tension and microenvironment that determine chemotaxis of the metastatic cancer cells.