Project Summary Densified fibrotic environments are commonly observed in aggressive solid tumors. The mechanisms and origins of these environments are not well understood despite their clinical relevance. Here, we take an integrated computational and experimental approach to decipher the mechanical mechanisms that lead to plastic, irreversible extracellular matrix (ECM) densification in the vicinity of tumors. We emphasize on the impact of dynamic cellular events, particularly dynamic local force generation, on ECM fiber kinetics that leads to spatiotemporal remodeling of the ECM network. We will perform high resolution time lapse imaging to quantitatively capture the force-induced densification of the ECM near tumor clusters, and we will perform computational simulations of dynamic 3D ECM networks to uncover mechanistic insights that govern this phenomenon. Finally, quantitatively guided by our computational and experimental findings, we will develop a novel drug delivery strategy that selectively targets the dynamic mechanical landscape of the tumor microenvironment.