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Childhood Cancer Data Initiative (CCDI): Metastatic Osteosarcoma snMultiome Profiling

Metastatic osteosarcoma is an aggressive bone malignancy affecting pediatric, adolescent, and young adults. While recent research has increasingly focused on understanding the complex biology of the osteosarcoma microenvironment, the tumor vasculature is understudied, especially in the context of metastatic disease. To address this, we performed single-nuclei multi-ome (RNA+ATAC) sequencing on a cohort of 24 human metastatic osteosarcoma specimens. Our data shows that endothelial cells universally exhibit a hybrid endothelial–mesenchymal state consistent with endothelial-to-mesenchymal transition (EndMT). Additionally, we uncovered that a subset of diploid endothelial cells adopts an osteoblastic cell fate as evidenced by gene expression and gene regulatory network (GRN) analysis. Joint copy-number analysis of our dataset identified a subset of osteosarcoma cells with endothelial transcriptional programs and GRNs, indicative of vascular mimicry. In vitro assays and in vivo lineage tracing experiments using syngeneic murine models validated both vascular mimicry and endothelial to-osteoblastic transdifferentiation. Collectively, these findings highlight the remarkable plasticity and lineage infidelity of both endothelial and osteosarcoma cells in patient specimens and a metastatic syngeneic murine model, provide novel insights into the functional role of endothelial cells in the metastatic osteosarcoma microenvironment, and challenge current understanding of osteosarcoma biology.