Abstract A35: Characterization of the genomic landscape of osteosarcoma metastasis

Abstract

Abstract Early metastasis to the lungs is a cardinal feature of osteosarcoma (OS), and complications from metastatic disease remain the most common cause of cancer-related death. Despite the prevalence of metastasis in OS, the pathogenesis is poorly understood. We have established a collection of 16 patient-derived xenografts (PDX) from human OS tumors, both from the primary site as well as metastasis. Our collection includes 9 diagnostic biopsies from primary site tumors, 2 primary tumor resections, 3 lung metastases, and 1 ascites fluid metastasis. Gene expression analysis of an initial set of 5 PDX models (3 metastases, 2 primaries) has been completed. A more extensive analysis of all 16 models by RNAseq and WGS is currently underway. Preliminary gene expression analysis identified a significant number of genes differentially expressed between metastatic samples and non-metastatic samples. This list included genes associated with cell adhesion and motility such as MEGF10, genes associated with endochondral ossification and bone remodeling such as RANKL, and genes associated with deposition of extracellular matrix (ECM) such as COL21A. Another candidate gene, ENPP1, is responsible for mineralization of the ECM and has been implicated in breast cancer metastasis to bone. We have validated differential expression of a number of these genes in independent samples of metastatic OS. We are currently using small hairpin RNA (shRNA), CRISPR, and overexpression vectors to knockdown, silence, and overexpress ENPP1 and other candidate genes in OS cell lines. Using in vitro migration and invasion assays as well as intravenous injection and orthotopic mouse models, we are characterizing the contribution of candidate genes to the metastatic propensity of OS. Citation Format: Amanda L. Koehne, Leanne C. Sayles, Marcus R. Breese, Dedeepya Vaka, Alejandro Sweet-Cordero. Characterization of the genomic landscape of osteosarcoma metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A35.