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

Abstract

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.

Magnetic-driven hydrogel microrobots for promoting osteosarcoma chemo-therapy with synthetic lethality strategy

“…Given that cell morphology, intercellular interactions, and cell polarity often undergo alterations in the two-dimensional culture system, rendering it challenging to emulate the authentic growth of tumor cells in vivo , the predictability of preclinical research predicated on this is limited ( Jubelin et al, 2022 ; Wang and Jeon, 2022 ). Three-dimensional cell culture, a novel cell culture methodology developed in recent years, can more accurately simulate the in vivo growth state of cells, and facilitate subsequent drug screening ( Jensen and Teng, 2020 ; Gonzalez Diaz et al, 2022 ). Consequently, we selected three-dimensional cell spheroid culture for subsequent experiments.…”

Enhanced Biomimetics of Three-Dimensional Osteosarcoma Models: A Scoping Review

“…Osteosarcoma cells were more resistant to anticancer drugs in the presence of a native ECM component [ 24 , 40 ] and in the presence of a complex matrix incorporating matrix components of the OS niche [ 27 ]. Furthermore, increasing osteomimetic native material such as HA results in higher drug resistance [ 69 ].…”

In vivoandIn vitroproperties evaluation of curcumin loaded MgO doped 3D printed TCP scaffolds

“…5 However, the large defects after surgical removal of osteosarcoma are beyond the bone's self-healing capacity and need to be reconstructed utilizing an artificial bone graft. 6,7 There is a need to develop a multifunctional bone graft that can have the dual properties of chemoprevention and new bone formation after osteosarcoma surgery. 8 Naturopathy is currently gaining importance in the medical community across the globe owing to its abundance and safety compared to commercial alternatives.…”