3D cell-matrix mechanical interaction models for cancer invasion

Cancer cells breach the extracellular matrix (ECM) through both protease-mediated degradation and force-driven physical remodeling, yet most invasion studies still rely on biochemical readouts that overlook how cells mechanically reorganize their surroundings. Here, we introduce a fully synthetic 3D invasion platform based on cellular force-responsive polyisocyanide (PIC) hydrogels that isolates biophysical invasion mechanisms. Cell-generated contractile forces align and densify the PIC fibrous network, recapitulating key features of matrix remodeling observed in the tumor microenvironment. A constitutive model incorporating the critical stress for strain stiffening links matrix nonlinear elasticity to pericellular stiffening, long-range force transmission, and intercellular mechanical communication. Using this system, we show that breast cancer cells can invade even under matrix metalloproteinases (MMP) inhibition, revealing a mechanical bypass of protease blockade. Consequently, broad-spectrum MMP inhibitors that appear effective in Matrigel fail to suppress invasion in PIC, highlighting limitations of current drug-evaluation platforms. In coculture, cancer-associated fibroblasts (CAFs) accelerate invasion by generating aligned, force-induced fiber tracks, underscoring the role of CAF-driven mechanical remodeling in metastasis. This thermoresponsive platform is compatible with standard Transwell formats, supports direct imaging of fiber architecture and invasion fronts, and decouples biophysical from biochemical cues, providing a mechanism-aware, animal-free approach for studying tumor invasion and evaluating anti-metastatic therapies.