Title: Advancing In Vitro Models of Osteosarcoma: The Impact of Scaffold Choice and Bone Niche Cells on Disease Phenotype and Drug Response

Abstract: Osteosarcoma (OS) is a rare yet aggressive primary bone cancer characterized by diverse genomic mutations and a high metastasis rate. Despite significant advancements in treatment for many other cancer types, therapeutic options for OS have remained stagnant for over four decades. A critical barrier to progress is the lack of scalable experimental models that accurately recapitulate OS biology and drug responses in vivo. Tissue-engineered 3D in vitro models offer a promising approach to bridging this gap, yet key challenges remain. First, previous studies used different biomaterials as scaffolds without direct comparison. Second, previous models generally include only the cancer cells. As such, the impact of scaffold choice and bone niche cell interactions on OS phenotype and drug responses in 3D remains largely unknown. 

This thesis addresses these challenges through two main projects. The first investigates how the choice of scaffold materials influences OS phenotype and drug response. By systematically comparing four biomaterials commonly used in bone tissue engineering, we demonstrate that scaffold choice significantly affects OS cell proliferation, extracellular matrix deposition, and chemoresistance. The second project examines the impact of interactions with osteoblasts, a key bone niche cell type, on OS behavior. Our results reveal that co-culturing OS cells with MSC-derived osteoblasts in 3D enhances resistance to gemcitabine, a chemotherapy used in OS treatment. Ongoing work seeks to further investigate the mechanisms that drive such drug resistance. In summary, this thesis provides valuable insights into the role of scaffold selection and bone niche cell interactions in OS biology and drug responses. These findings will help guide the advancement of 3D in vitro OS models with improved physiological relevance for high-throughput drug screening, ultimately accelerating the discovery of more effective treatments for this devastating disease.

Please contact Madelyn Bernstein for the Zoom link.