Defining Integrin Tension Required for Chemotaxis of Metastatic Breast Cancer Cells in Confinement

Abstract

Cancer metastasis is affected by chemical factors and physical cues. From cell adhesion to migration, mechanical tension applied to integrin expresses on the cell membrane and physical confinement significantly regulates cancer cell behaviors. Despite the physical interplay between integrins in cells and ligands in the tumor microenvironment, quantitative analysis of integrin tension during cancer cell migration in microconfined spaces remains elusive owing to the limited experimental tools. Herein, a platform termed microconfinement tension gauge tether to monitor spatial integrin tension with single‐molecule precision by analyzing the epithelial‐growth‐factor‐induced chemotaxis of metastatic human breast cancer cells in microfluidic channels is developed. The results reveal that the metastatic cancer cells exert the strongest integrin tension in the range of 54–100 pN at the leading edges of cells during chemokinetic migration on a planar surface, while the cells exert the strongest integrin tension exceeding 100 pN at the cell rear when entering microconfinement. Further analysis demonstrates that cells undergo mesenchymal migration under high integrin tension and less confinement, which is converted to amoeboid migration under low integrin tension or high confinement. In summary, the results identify a basic mechanism underlying the mechanical interactions between integrin tension and microenvironment that determines cancer invasion and metastasis.

Mesenchymal cell migration on one-dimensional micropatterns

“…In particular, motion of mesenchymal migration is restricted by an adhesive pattern, as shown in Figure 1A . Adhesive patterns are typically functionalized with an extracellular matrix (ECM) protein such as fibronectin or collagen while the space in between patterns is blocked using cell-repellent block-copolymers such as poly(L-lysine) grafted poly(ethylene glycol) (PLL PEG) ( Schreiber et al, 2016 ; Schuster et al, 2016 ; Ljepoja et al, 2019 ; Zhou et al, 2020 ; Monzo et al, 2021 ; Kim et al, 2023 ). The width of the 1D microlanes is a critical parameter and determines the mode of migration ( Schreiber et al, 2016 ; Ljepoja et al, 2019 ).…”

Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis

“…Furthermore, a micro-confinement TGT (µC-TGT) has been developed to comprehend alterations in integrin-mediated force during cell migration and adhesion within restricted microchannels. Elevated integrin tension and reduced confinement induce mesenchymal migration of breast cells ( Kim et al, 2023 ). These findings indicate the influence of pico Newton forces transmitted through integrins on the regulation of cancer cell proliferation and metastasis.…”