A novel mechanobiological model of bone metastasis reveals that mechanical stimulation inhibits the pro-osteoclastogenic effects of breast cancer cells

Tumor metastasis into bone alters the biomechanical cues experienced by both tumor and native bone cells (osteoblasts, osteoclasts and osteocytes). Both bone and tumor cells are regulated by mechanical stimuli, yet the mechanobiological role bone and tumor cells play in driving osteolysis are not yet fully understood. Here, 3D in vitro co-culture and computational models were developed to investigate the coupled influence of tumor-bone cell signaling and growth induced matrix stress on tumor growth. We also developed advanced in vitro 3D models of the in vivo multicellular and mechanical environment and confirmed the ability of this model to recapitulate osteoblast, osteoclast and metastatic activity. We applied this bone metastasis model to investigate how interactions between tumor and bone cells, and their surrounding biophysical environment dictate osteolysis and tumor development. Our results revealed that tumor spheroid growth is regulated by the synergistic influence of bone cell signaling and matrix stiffness. We also demonstrate for the first time the importance of mechanical loading in attenuating breast cancer cell activity and signaling for osteoclastogenesis during early stage bone metastasis.