Ng, P. K. S. | Search bioRxiv

bioRxiv2025

Satellite DNA fragility accompanies complex genome rearrangements and ecDNA oncogene amplification in canine osteosarcomas

Canine osteosarcoma (OS) is an aggressive bone cancer with remarkable similarity to human OS. Despite its value as a comparative oncology model, the drivers of genomic instability remain poorly defined, hindering cross-species insights into disease progression. We applied long-read PacBio HiFi whole genome sequencing to matched tumor and blood samples from four purebred dogs to generate high-resolution maps of somatic structural variants (SVs). Tumor genomes showed extensive rearrangement complexity, with satellite repeat regions, particularly SAT1_CF, enriched near somatic SV breakpoints and occurring within genomic contexts marked by focal hypomethylation. We also identified multiple extrachromosomal DNA (ecDNA) elements carrying oncogenes indicating ecDNA-mediated oncogene amplification. Together, these data provide an integrated genomic and epigenomic view of canine OS, implicating satellite repeats as recurrent substrates for rearrangement and ecDNA as a prominent mode of genome remodeling. This work advances our understanding of OS genome dynamics and establishes a comparative framework for investigating repeat-driven instability and oncogene amplification across species.

genomics↗

bioRxiv2023

Immunosuppressive tumor microenvironment of osteosarcoma

Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy-number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously-published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for validation of discovered subtypes and to add spatial context. Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T-cells, and LAMP3+ dendritic cells. Using cell-cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-{kappa}B upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T-cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche. Statement of SignificanceOsteosarcoma patient survival has remained stagnant for several decades due to lack of successful therapy for high-risk patients, including those with metastatic disease. Identifying novel therapeutics including immunotherapies is of great clinical importance. Our study highlights several important immunosuppressive mechanisms within osteosarcoma that should be considered when developing future immunotherapies.

cancer biology↗