Abstract A6: Dissecting mechanisms of RANKL dependency in osteosarcoma

Abstract

Abstract Osteosarcoma is the most common bone tumor in adolescents, severely impacts quality of life, and ∼40% of patients die of metastases to lungs and liver. In an effort to study this poorly understood cancer, we have generated a novel transgenic mouse model of osteosarcoma (designated MOTO) through osteocalcin promoter-driven SV40 T-antigen expression. The MOTO model is 100% penetrant and recapitulates all critical features of the human disease including skeletal tumor distribution, radiology, histology, genomic instability and metastasis. Using genomic screens, we have identified the cytokine RANKL (Receptor Activator of Nuclear Factor kappa B Ligand), and its receptor RANK, to be aberrantly expressed in MOTO tumors and cell lines. Genetic studies using RANKL deficient MOTO mice reveal osteosarcoma to be broadly dependent on its expression. To further dissect the role of RANKL signaling in osteosarcoma, we have performed gain- and loss-of-function studies to determine if RANKL affects classic oncogenic cell parameters. Specifically, loss of RANKL in MOTO tumor cell lines inhibits invasion and soft agar colony formation, indicating its ability to contribute to tumorigenesis in a cell autonomous manner. To support this hypothesis, we are testing the effects of de novo RANK expression on the tumorigenic properties of osteoblastic cells. Together, these studies are dissecting the individual contributions of RANKL and RANK in controlling primary bone tumorigenesis. Citation Information: Cancer Res 2009;69(23 Suppl):A6.