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Elucidating the role of matrix stiffness

This coupling is particularly problematic given that matrix-imposed steric barriers can regulate invasion speed independent of mechanics.

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Our goal is to elucidate the molecular mechanisms that govern the mechanics of these networks, and to use this understanding to engineer biomaterials with useful mechanical properties for use in tissue engineering and other applications.Further, the processes of cell division and cell migration, which drive tumor growth, invasion, and metastasis, are by nature physical processes involving the spatiotemporally coordinated generation of force by cells on extracellular matrix.We are using engineered materials for 3D culture and atomic force microscopy to elucidate how cells generate forces to drive cell division and migration during tumor growth and metastasis.Inhibition of nonmuscle myosin II dissipates this traction polarization and renders the relationship between migration speed and ECM stiffness comparatively insensitive to matrix confinement.We test these hypotheses in silico by devising a multiscale mathematical model that relates cellular force generation to ECM stiffness and geometry, which we show is capable of recapitulating key experimental trends.Cell migration through the ECM may be regarded as a cyclic process that includes leading-edge extension of protrusions driven by actin polymerization, formation of cell-ECM adhesions, and trailing-edge retraction due to actomyosin contractility.

While ECM-based biophysical cues have been demonstrated to influence all of these steps (5), ECM stiffness has emerged as a particular parameter of interest given the observations that tumors are frequently more rigid than normal tissue and that exogenous tissue stiffening can facilitate tumorigenesis (6–13).

Many biological materials, from the actin cytoskeleton inside cells, which governs their shape and rigidity, to the extracellular matrix, consist of semiflexible biopolymer networks.

These networks are typically organized in specific architectures, and are often under tensional or compressional forces.

These studies represent a paradigm for investigating matrix regulation of invasion and demonstrate that matrix confinement alters the relationship between cell migration speed and ECM stiffness.

Tumor cells exploit a variety of migration strategies to invade tissue and metastasize to distant anatomical sites, which in turn requires specific biochemical and biophysical interactions between these cells and the extracellular matrix (ECM) (1–4).

We have successfully built a prototype high-speed confocal microscope and are currently building the next generation.