Cell migration and cell-matrix interactions have traditionally been studied in the context of 2D environments, where cells are cultured on artificial two-dimensional surfaces. While a number of key cellular and molecular parameters can be studied and quantified accurately with these classical approaches, a comprehensive and systems level understanding of cell migration requires quantification forces, signals and molecular interactions in native like 3D environments. In particular, the mechano-chemical effects of the matrix, the proteolytic pathways and surface receptor dynamics on a 3D surface have all shown to be critical in invasion and tumor metastasis, and can not be fully studied in a 2D environment.

In order to overcome the limited powers of observation in 2D, we utilize a combination of high resolution and high throughput confocal microscopy, bulk and micro-rheological measurements and multi-scale simulations rooted in statistical and continuum mechanics to understand the mechanical and chemical roles of the matrix in regulating cell motility. Our results show that in addition to adhesion and tractile forces, matrix stiffness is a key factor that influences cell movement in 3D in a number of fibrosarcoma, breast and prostate cancer cell lines. We also observe that 3D environments play a far more critical role in modulating cellular viscoelasticity than 2D substrates. Cellular response to minor mechanical changes in its extra-cellular environment is also amplified in 3D than in 2D environments. Our experimental results are complemented by multi-scale simulations, that predict and quantify the synergestic role of receptor-ligand interactions, matrix mechanics and adhesive forces in regulating motility. Our hybrid approach, combining high-resolution experimental and computational techniques demonstrates how a balance of cellular parameters (e.g. integrin expression and MMP activity) co-operate with matrix properties (e.g. composition, stiffness and porosity) to regulate invasion and motility of tumor cells in 3D environments.