Biophysical regulation of tumor cell invasion: moving beyond matrix stiffness

Invasion of cancer cells into the extracellular matrix (ECM) is a key step in tumor infiltration and metastasis. While the strong influence of ECM stiffness in governing tumor cell migration has been well established in two-dimensional culture paradigms, investigation of this parameter in three-dimensional (3D) ECMs has proven considerably more challenging, in part because perturbations that change 3D ECM stiffness often concurrently change microscale matrix parameters that critically regulate cell migration, such as pore size, fiber architecture, and local material deformability. Here we review the potential importance of these parameters in the context of tumor cell migration in 3D ECMs. We begin by discussing biophysical mechanisms of cell motility in 3D ECMs, with an emphasis on the cell-matrix mechanical interactions that underlie this process and key signatures of mesenchymal and amoeboid modes of motility. We then consider microscale matrix physical properties that are particularly relevant to 3D culture and would be expected to regulate motility, including matrix microstructure and nonlinear elasticity. We also discuss how changes in 3D matrix properties might be expected to trigger transitions in subcellular mechanisms, which in turn contribute to mesenchymal-amoeboid transition (MAT) by imposing restrictions on 3D motility. We expect that the field will gain valuable insight into invasion and metastasis by deepening its understanding of microscale, biophysical interactions between tumor cells and matrix elements and by creating new 3D scaffolds that permit orthogonal manipulation of specific matrix parameters.