Abstract A85: Novel mouse models to investigate the molecular pathogenesis of metastatic osteosarcoma

Abstract

Abstract Background: Osteosarcoma (OS) is the primary bone tumor in the pediatric population with the main determinant for patient prognosis being the presence of metastatic disease. Approximately 25-30% of patients will present with metastatic osteosarcoma. Patients with metastatic disease have long-term survival rates often <20%. Objectives: We hypothesize that the molecular pathogenesis of metastatic osteosarcoma is different from localized disease. We intend this work to provide a relevant, endogenous model of metastatic OS that can be utilized to advance our understanding of the molecular pathogenesis of the disease, insights into novel therapeutic targets and as a pre-clinical model for investigating the efficacy of novel therapies. Design: We have developed a tissue-specific alteration of the p53 status by using osteoblast specific Cre-recombinase expressing mice to generate progeny that spontaneously form endogenous osteosarcomas. Through the use of a mutated, gain of function form of p53, shown previously to be associated with metastatic disease, we have developed a novel immunocompetent model that significantly enhances the endogenous development of metastatic OS. Results: Tumor analysis has revealed genetic insights in the metastatic progression of osteosarcoma. These include the significant downregulation of Wnt-signaling inhibitors, such as NKD2, APCDD1 and Wnt5a in the metastatic tumors. Functional studies have determined that overexpression of NKD2, also downregulated in several human OS metastatic cell lines, in metastatic mouse OS cell lines leads to a significant decrease in metastatic lung lesions upon transplantation into immunodeficient mice. Possible NKD2-dependent functions include regulation of not only the Wnt signaling pathway, but also blood vessel formation, regulation of cell migration and cell adhesion. We have also noted the dysregulation of several critical microRNAs in metastatic OS, including the upregulation of mir-130b in the metastatic lesions. This particular microRNA has recently been shown to have clinical correlation in Ewing's sarcoma, with higher levels of tumor mir-130b having a significantly poorer outcome. We are actively pursuing the role of this (and other) microRNA(s) in the molecular pathogenesis of metastatic osteosarcoma. Conclusion: This novel model has enabled valuable molecular insights into the development and progression of metastatic OS that can lead to the identification of novel therapeutic targets. Citation Format: Shuying Zhao, Lyazat Kurenbekova, Lawrence A. Donehower, Jason T. Yustein. Novel mouse models to investigate the molecular pathogenesis of metastatic osteosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A85.