Development and Characterization of Novel Models of Human Osteosarcoma Development and Metastasis
Background: Osteosarcoma is the most common cancer of the bone in children and adolescents, with approximately 900 new cases annually in the United States. It occurs largely in growing adolescents and young adults, with the highest incidence at the age of 15-19-years-old. Surgery, chemotherapy, and radiation remain the most common therapeutic interventions but are associated with significant side effects that negatively impact patient quality of life. A better understanding of the genetic mechanisms and underlying biological events involved in the initiation and development of osteosarcoma would pave the way for the development of new therapies. However, effective models of human osteosarcoma initiation and development are not available and thus these fundamental questions go unanswered.
Project Goal: The current proposal will implement cutting edge technologies in the area of pluripotent stem cell-based tissue engineering to replicate bone formation in a dish, and couple this strategy with advanced methods for genome engineering to model mutations that are suspected to promote the formation of osteosarcoma. This system will represent a novel and highly impactful platform for functional studies elucidating the mechanisms underlying human osteosarcoma initiation, development, and metastasis. Additionally, while the current proposal focuses on osteosarcoma, in theory, our pluripotent stem cell-based platform can be used to model cancers derived from nearly any tissue type. Consequently, the proposed research has far-reaching implications for the way all human cancers are studied and will undoubtedly foster the development of clinically relevant therapeutic interventions.
Project Update 2021: Through three years of ALSF support we have made substantial progress in our efforts to model osteosarcoma (OS) development with human induced pluripotent stem cells (iPSC). We have further characterized the specific cell types present in our iPSC-MSC cultures and developed optimized gene engineering methods in order to “install” mutations implicated in OS. We have shown that osteoblasts derived from engineered iPSC exhibit properties of transformation including the ability to form aggressive sarcomas in mice. We are currently characterizing these tumors at the molecular and histological level to determine how closely they resemble patient-derived osteosarcoma. We have also observed that our system replicates genomic instability that is a hallmark of OS development, and we are currently conducting studies to better understand this process. Ultimately, we are confident that the model we have developed will allow us to gain a greater understanding of what causes OS to form, and why some patient’s OS is more difficult to treat than others. Most importantly, this model and the knowledge gained from it will ultimately allow more rapid testing of new therapeutic interventions.
