Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
Division of Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, California, 94143, USA.
Adv Healthc Mater. 2022 Sep;11(17):e2200768. doi: 10.1002/adhm.202200768. Epub 2022 Jul 10.
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.
骨肉瘤（OS）是一种侵袭性骨癌，三十多年来其生存率没有提高。虽然生物材料已被广泛用于工程化 3D 软组织肿瘤模型，但利用工程化 3D 基于生物材料的骨肉瘤模型来全面研究骨肉瘤病理学和药物发现的潜力尚未得到开发。骨骼的特征是矿物质含量高，但骨矿物质在骨肉瘤进展和药物反应中的作用尚不清楚。在这里，开发了一种基于微带的具有仿生成分的骨肉瘤模型，以阐明 3D 培养和羟磷灰石在骨肉瘤信号转导和药物反应中的作用。结果表明，3D 中的羟磷灰石对于支持骨肉瘤信号转导和耐药性的保留至关重要，这与患者组织和小鼠原位肿瘤相似。使用四个已建立的骨肉瘤细胞系、七个患者来源的异种移植（PDX）细胞系和两种动物模型验证了该 3D 模型的生理相关性。将 3D 骨肉瘤 PDX 模型与 RNA 测序相结合，确定了 3D 特异性可用药靶，该靶可预测小鼠原位模型中的药物反应。这些结果确立了基于微带的 3D OS 模型作为一种新的实验工具，可用于发现否则会被 2D 模型遗漏的新型治疗方法，并且可以作为研究患者特异性骨肉瘤异质性和耐药机制的平台。
