Abstract
Breast cancer is the most common cancer and the second leading cause of cancer-related death in women. In advanced stages of the disease, breast cancer can spread and metastasize to the bone, contributing to malignant progression. The roles of tissue stiffness and remodeling of the tumor microenvironment are relevant in influencing cancer progression and invasiveness, but they are still poorly understood. In this study, we aimed to investigate the effect of bone tissue stiffness on breast cancer cell behavior, using 3D cell-biomaterial systems to model the in vivo conditions. For this purpose, we developed a 3D-printable cell array, which is a tunable and reproducible platform on small scale, where each compartment could mimic the physiological cancer environment with a shape and rigidity close to bone tissue. In this system, we observed that in the highly metastatic breast cancer line MDA-MB-231, embedded in PEG-silk fibroin (PSF) hydrogel spheres in the array's cavities, increasing stiffness promotes trans-differentiation into osteoblast-like cells and the production of breast microcalcifications. Moreover, we also tested this 3D model as a platform to evaluate the cell response to the therapy, in particular, investigating the drug sensitivity of the cancer cells to chemotherapeutics, observing a decrease in drug resistance over time in the array.