The Role of Notch Pathway in Bone Development and Osteosarcoma

Human osteosarcoma (OS) is an aggressive mesenchyme-derived tumor associated with high mortality that affects mostly adolescents. Lack of understanding of the genetic factors and pathways critical for OS formation and metastasis impedes the progress of developing effective, therapeutic strategies to treat this malignant disease. The p53 gene, which is mutated in more than 50% of human tumors, has been reported as a driver mutation in mouse models of human OS. Recently, our and other studies suggest that activation of Notch signaling not only can serves as a driver mutation of murine OS, but also contributes to the pathogenesis of human OS. Notch signaling plays an important role in developmental processes and adult tissue homeostasis by regulating cell fate determination, proliferation, differentiation and apoptosis. Altered Notch signaling has been associated with several cancers and can act both as an oncogene and tumor suppressor gene depending on its expression levels and timing. More recently, Wnt pathway has been implicated in OS progression and its inhibition may be a therapeutic approach for the treatment of human OS. In our proposal, we hope to understand the genetic links among p53, Notch, and Wnt signaling to develop a comprehensive portrait of the genetic changes that lead to OS formation. We will generate a series of different gain and/or loss of gene function mouse models to determine whether OS initiation and progression would be affected. Success of this proposal will have an important positive impact on clinical application because it will identify a genetic role of Notch and Wnt signaling in development of OS. The proposed Specific Aims will address two fundamental questions: 1) how do genetic pathways such as p53, Notch and Wnt initiate and promote tumor formation; and 2) what are the mechanisms that maintain bone cancer stem cells and promote metastasis? In addition, these studies will provide the genetic mechanistic framework of how Notch and Wnt signaling interact in the context of bone cells. Eventually, understanding the genetic pathways and their interaction will lead to development of treatment strategies to target those genes and facilitate novel approaches to improve children's health.