A 3D Osteosarcoma Model with Bone‐Mimicking Cues Reveals a Critical Role of Bone Mineral and Informs Drug Discovery

Osteosarcoma (OS) is an aggressive bone cancer for which survival has not improved over three decades. While biomaterials have been widely used to engineer 3D soft-tissue tumor models, the potential of engineering 3D biomaterials-based OS models for comprehensive interrogation of OS pathology and drug discovery remains untapped. Bone is characterized by high mineral content, yet the role of bone mineral in OS progression and drug response remains unknown. Here, a microribbon-based OS model with bone-mimicking compositions is developed to elucidate the role of 3D culture and hydroxyapatite in OS signaling and drug response. The results reveal that hydroxyapatite in 3D is critical to support retention of OS signaling and drug resistance similar to patient tissues and mouse orthotopic tumors. The physiological relevance of this 3D model is validated using four established OS cell lines, seven patient-derived xenograft (PDX) cell lines and two animal models. Integrating 3D OS PDX models with RNA-sequencing identified 3D-specific druggable target, which predicts drug response in mouse orthotopic model. These results establish microribbon-based 3D OS models as a novel experimental tool to enable discovery of novel therapeutics that would be otherwise missed with 2D model and may serve as platforms to study patient-specific OS heterogeneity and drug resistance mechanisms.