Breast-cancer and Prostate-cancer are among the most prevalent cancers in women and men, respectively. The World-Health-Organization estimates that about a million deaths occur due to breast and prostate-cancer worldwide due to these cancers each year. Although mostly curable when detected early at the primary site, both of these cancers are incurable when the cancer metastasizes to a distant location in the body, which for these two cancers is eventually bone. There is a scarcity of available human samples and animal models fail due to death preceding bone metastasis; hence a huge unmet need for development of robust in vitro models of bone metastasis. We have developed a novel testbed using a bone mimetic nanoclay scaffold to regenerate human bone followed by sequential seeding prostate and breast-cancer cells obtained from commercial and patient derived cell lines to generate tumors. Extensive analysis of the tumors using gene and protein expression assays and imaging confirm that the testbeds can replicate tumors during mesenchymal-to-epithelial-transition (MET). While many biomarkers exist for evaluation of cancer at the primary site, there are no known bone metastasis markers. Mechanical properties of cells and tissues can capture the complex biological phenomena of adhesion and colonization at the bone site. We also observe via imaging, significant changes to the cytoskeleton quantity and organization within the cells as cancer progresses at bone metastasis. We measured mechanical response of cells using direct-nanoindentation experiments on cancer cells from tumors generated on the testbeds to describe the evolution of cellular properties during cancer progression at the bone metastasis sites. We conducted the nanoindentation experiments under static and dynamic modes to evaluate elastic moduli, hardness, and viscoelastic properties of cancer cells over time. The force-displacement response, elastic moduli, hardness, plastic deformation, viscoelastic properties were captured, with confocal imaging of the cytoskeleton and gene and protein expressions at the same time points. Our results indicate significant reduction in elastic modulus and increased fluid-like behavior of bone metastasized breast-cancer cells (MCF-7) caused by depolymerization and reorganization of F-actin. On the other hand, bone metastasized triple negative cells (MDA-MB-231) showed insignificant changes in elastic modulus and F-actin reorganization over time. We also measured changes to nanomechanical properties of MDA PCa2b(PCa) prostate-cancer cells during the MET and cancer bone metastasis progression over time. The stiffness of PCa cells decreases with metastasis; however, the mechanical plasticity increases during the same time, suggesting that PCa cells become softer on undergoing MET and softer with metastasis progression. In all cases, the imaging and gene, protein expression studies, and computational modeling point towards the depolymerization of actin and reorganization of the cytoskeleton as key factors in the evolution of cell mechanics. In addition, we also subjected the cancer cells to physiologically relevant fluid induced shear stresses that are experimentally enabled using specially designed bioreactors as well as computationally modelled. The role of fluid-derived stresses on migratory characteristics and apoptosis potential of cells is also evaluated. These studies present the use of mechanics-based characterizations as a potential new tool for evaluation of metastasis progression.