Modeling the natural history of bone metastasis from breast cancer in a 3D biomimetic scaffold

The study of bone metastasis from breast carcinoma is hampered by the lack of in vitro models that recapitulate the complex sequential stages and interactions between tumor cells and microenvironment. Animal models could be useful for evaluating the complexity of the bone metastasis process, but this model suffers of being time-consuming and labor intensive. To date, there is no ideal animal model able to replicate different aspects of the metastasis, such as the pre-metastatic niche formation in the host secondary organ. Hence, it emerges the need to fill the gap between in vitro and in vivo model with a reliable in vitro three-dimensional (3D) system that closely recapitulates the complexity of the bone microenvironment and its interaction with cancer cells. With a step-by-step approach, we aimed to mimic the mechanisms involved in the natural history of breast cancer bone metastasis, from the establishment of the pre-metastatic niche to the bone metastasis. To achieve this aim, we developed a bone 3D biomimetic scaffold, made of collagen, and functionalized with hydroxyapatite material, able to mimic the composition of the bone matrix in vitro. We demonstrated that this platform is suitable for the culture and differentiation, from their respective precursor cells, of osteoclasts and osteoblasts. Then, we investigated how the bone biomimetic extracellular matrix can affect dynamics of cell growth, genetic and phenotypic characteristics of three breast cancer cells lines. Interestingly, different extracellular matrix (ECM) seems to affect breast cancer and osteoclasts sensitivity to bone targeted drugs. The achieved results represent a first step, which laid the ground to a more comprehensive model. A more understanding of the mechanisms underlying these processes would help the identification of future therapeutic strategies that specifically target defined components of the bone microenvironment to prevent or treat skeletal metastases.