Intrinsic epigenetic state of primary osteosarcoma drives metastasis [ATAC-seq]
Osteosarcoma (OS) is a primary malignant bone tumor commonly affecting children, adolescents, and young adults with a potential to metastasize to distal sites, most commonly lung. Here, we mapped the active chromatin landscapes of OS patients with varying extent of disease. We integrated histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) of OS tumors from four different diseased states to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary tumors that undergo metastasis (primary mets) have a distinct enhancer landscape compared to primary tumors that remain localized (localized) during the course of disease. The difference in chromatin activity shapes the transcriptional profile of OS patients. Some of the genes like PPP1R1B, PREX1 and IGF2BP1 whose role in OS pathogenesis and metastasis remains poorly understood, exhibit increased enhancer activity in primary mets along with higher RNA levels. Genome-wide loss-of-function screens also reveal these genes to be as selective dependencies in bone sarcomas, making them promising candidates for further investigation. Overall, differential chromatin activity in primary mets occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and migration process suggestive of their role in facilitating OS metastasis. Thus, this data demonstrates that metastatic potential is intrinsically present in primary mets OS much before the occurrence of metastasis and when the cells are presented with favorable conditions to migrate and colonize at a distant site, they under undergo metastasis. Overall design: Comparison of the chromatin accessibility profiles of osteosarcoma tumors from four different diseased states (primary met, lung met, localized, and local control) integrated with gene expression and  histone H3K27ac profiles to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving malignant phenotypes