Introduction:: Breast cancer becomes invasive when carcinoma cells invade through the basement membrane (BM), a nanoporous layer of matrix that physically separates the primary tumor from the stroma. Single cells can invade through nanoporous three-dimensional (3D) matrices via protease-mediated degradation or force-mediated widening of pores via invadopodial protrusions. However, how multiple cells collectively invade through physiological BM layers, as they do during breast cancer progression, remains unclear.
Materials and Methods:: Here, we developed a 3D in vitro model in which mammary epithelial acini were encapsulated in matrigel-alginate interpenetrating networks of soft and stiff environments to mimic healthy and cancerous tissues respectively. Using live fluorescent labeling of endogenous BM, we investigated physical interactions between endogenous BM and mammary epithelial cells leading to invasion. To investigate the physical mechanism of these interactions, we use various techniques such 3D traction strain microscopy, FRET sensors, and 3D cell volume measurements .
Results, Conclusions, and Discussions:: We show that cells utilize both proteases and forces, but not invadopodia, to breach the BM. Forces are generated from a combination of global cell volume expansion, which stretches the BM, and local contractile forces that act in the plane of the BM to breach it, allowing invasion. These results uncover a mechanism by which cells collectively interact to overcome a critical barrier to metastasis.
