Abstract 6833: Microenvironment-specific transcriptomic changes in osteosarcoma metastasis

Abstract Osteosarcoma (OS) is the most common primary malignancy of bone in children and adolescents. While conventional chemotherapy has improved 5-year survival rates for localized disease to 70%, metastatic disease remains at 20-30%. Failure of modern treatment options to improve survival reflects the failure of agents that appear promising in preclinical models to demonstrate clinical efficacy in human patients. We hypothesize that this is because most preclinical testing is performed on tumors implanted subcutaneously in immune deficient mice. Our previous work has shown that tumors implanted subcutaneously do not metastasize, whereas genetically identical tumors implanted orthotopically (in the tibia) metastasize to lungs and bones. Thus, to better understand non-genetic drivers of metastasis, we implanted patient-derived xenografts (PDXs) either orthotopically or subcutaneously into NSG mice. Once tumors reached 1.5cm, tumors were extracted along with distant metastases and analyzed by single-cell RNA sequencing. Transcriptomic analysis reveals 1) that fragments of the same tumor implanted subcutaneously have a vastly different transcriptome than fragments implanted orthotopically, 2) the transcriptome of distant metastases is dramatically different from the transcriptome of the primary tumor, and 3) the gene expression profile of metastases is different in different metastatic sites. In all 3 of these circumstances, these differences reflect differences in differentiation status, signaling pathway activation, and immune cell infiltrate. Thus, we conclude that the environment in which a tumor grows significantly alters its gene expression and phenotype. Our study highlights the need for careful consideration of the tumor microenvironment when designing pre-clinical studies to ensure accurate representation of human osteosarcoma and may help to explain the dismal record of translating novel agents from preclinical studies into standard therapy. Citation Format: Shimara Gunawardana-Zeigler, Dan Peng, Patrick Cahan, David Loeb. Microenvironment-specific transcriptomic changes in osteosarcoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6833.