Dual-Lineage Human 3D Bone Niche Model Reveals Osteoclast-Driven Osteomimicry in Prostate Cancer

Bone is the predominant site of metastasis in advanced prostate cancer (PCa), yet the mechanisms governing tumor-bone interactions remain incompletely understood. A modular human three-dimensional (3D) in vitro bone niche model is developed that integrates osteoblasts and osteoclasts within a mineralized scaffold, recreating an endosteal-like microenvironment for co-culture with PCa cell lines and patient-derived organoids (PDOs). The engineered construct maintains osteoblastic differentiation and supports osteoclastogenesis, confirmed by lineage markers including osteocalcin, osteopontin (OPN), and tartrate-resistant acid phosphatase (TRAP). Co-culture with PCa cells downregulates osteoblast- and osteoclast-associated genes (IBSP, OPN, TRAP) in bone cells, suggesting tumor-mediated suppression of bone remodeling. Conversely, co-cultured PCa cells exhibit niche-dependent osteomimicry, characterized by upregulation of osteoblastic (SPARC, BGLAP) and osteoclastic (TRAP) markers and strongly regulated by the presence of osteoclasts. The platform also supports engraftment and proliferation of PDOs without PCa-specific exogenous growth factors, underscoring its translational relevance. This osteoblastic-osteoclastic niche model thus provides a human system capturing PCa-bone cell interactions, with potential utility to investigate therapeutic responses in a clinically relevant context.