Cell invasion into the surrounding matrix from nonvascularized primary tumors is the main mechanism by which cancer cells migrate to nearby blood vessels and metastasize to eventually form secondary tumors. This process is mediated by an intricate coupling between intracellular forces and extracellular forces that depend on the stiffness of the surrounding stroma and the alignment of matrix fibers. A multiscale model is used to elucidate the two-way feedback loop between stress-dependent cell contractility and matrix fiber realignment and strain stiffening, which enables the cells to polarize and enhance their contractility to break free from the tumor and invade into the matrix. Importantly, Dr. Shenoy’s model can be used to explain how morphological and structural changes in the tumor microenvironment, such as elevated rigidity and fiber alignment prior to cell invasion, are prognostic of the malignant phenotype. The model also predicts how the alignment of matrix fibers can recruit macrophages, which are among the first responders of the innate immune system following organ injury and are crucial for repair, resolution, and re-establishing homeostasis of damaged tissue. In this talk, Shenoy will discuss how the deformation of the nucleus during migration can lead to changes in the spatial organization of chromosomes and their intermingling which can result in genetic mutations and genomic instability. He will also discuss how targeting extracellular matrix mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response in cancer and fibrosis, is a therapeutic approach with clinical potential.