Probing the mechanisms of dependency underlying skeletal genetic pathways of p53 and Notch in the pathogenesis of osteosarcoma - Project Summary The goal of this proposal is to understand cancer dependency pathways that regulate premalignant osteoblasts and the development of osteosarcoma. Osteosarcoma originates from cells of the osteoblast lineage and is a fatal bone tumor that occurs primarily in children. Clinical outcomes for human osteosarcoma patients with tumor recurrence or metastatic spread are devastating. Elucidating cancer-dependent skeletal genes and pathways in osteosarcoma is critical for the development of effective new therapies. Multiple lines of evidence indicate that tumor protein p53 and Rb mutations are major drivers of osteosarcoma in patients with Li-Fraumeni family cancer syndrome and hereditary retinoblastoma, as well as in the majority of patients with sporadic osteosarcoma. However, how dependent genes and pathways in osteosarcoma promote proliferation, differentiation, and metastasis is unclear. We have recently developed several osteoblast-specific genetically engineered mouse models (GEMMs) of osteosarcoma tumors that recapitulate the defining features of human osteosarcoma, including cytogenetic complexity, gene expression signatures, histology, and metastatic behavior. These models provide powerful tools for understanding the above clinical challenges and developing new treatment strategies. Our preliminary studies in mouse and human osteosarcoma cells uncover a link between cancer-dependent pathways and osteosarcoma progression. Validation of these findings will greatly facilitate clinical applications. Based on these findings, we hypothesize that cancer-dependent skeletal genes and pathways play critical roles in osteosarcoma progression. Furthermore, perturbation of cancer-dependent pathways may contribute to osteosarcoma metastasis and cancer therapy. We will test this hypothesis through two specific aims. 1) Investigating the role of cancer-dependent skeletal genes and pathways in osteoblast-specific p53 and Rb loss- of-function models; 2) Assessing the potential for manipulation of cancer-dependent skeletal genes and pathways to treat GEMMs as well as human osteosarcoma xenograft models. As this work is completed, we will have a more complete understanding of the molecular mechanisms underlying the role of cancer-dependent skeletal pathways in osteosarcoma growth and progression. Additionally, we will gain improved rationales for the use of preclinical and/or clinical agents in pediatric cancer treatment, as well as new insights into how to improve the efficacy of chemotherapeutic agents.
