High-Throughput Transcriptomics Identifies Chemoresistance-Associated Gene Expression Signatures in Human Angiosarcoma

Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, including 35 cases treated with palliative chemotherapy, integrating information from NanoString gene expression profiling, whole transcriptome profiling (RNA-seq), immunohistochemistry, cell line assays, and clinicopathological data. In the chemoresistant cohort (defined as stable disease or progression), we observed the significant overexpression of genes, including <i>SPP1</i> (log2foldchange 3.49, adj. <i>p</i> = 0.0112), <i>CXCL13</i>, <i>CD48</i>, and <i>CLEC5A</i>, accompanied by the significant enrichment of myeloid compartment and cytokine and chemokine signaling pathways, as well as neutrophils and macrophages. RNA-seq data revealed higher <i>SPP1</i> expression (<i>p</i> = 0.0008) in tumor tissues over adjacent normal compartments. Immunohistochemistry showed a significant moderate positive correlation between <i>SPP1</i> protein and gene expression (r = 0.7016; <i>p</i> < 0.00110), while higher <i>SPP1</i> protein expression correlated with lower chemotherapeutic sensitivity in patient-derived angiosarcoma cell lines MOLAS and ISOHAS. In addition, <i>SPP1</i> mRNA overexpression positively correlated with epithelioid histology (<i>p</i> = 0.007), higher tumor grade (<i>p</i> = 0.0023), non-head and neck location (<i>p</i> = 0.0576), and poorer overall survival outcomes (HR 1.84, 95% CI 1.07-3.18, <i>p</i> = 0.0288). There was no association with tumor mutational burden, tumor inflammation signature, the presence of human herpesvirus-7, ultraviolet exposure signature, and metastatic state at diagnosis. In conclusion, <i>SPP1</i> overexpression may be a biomarker of chemoresistance and poor prognosis in angiosarcoma. Further investigation is needed to uncover the precise roles and underlying mechanisms of <i>SPP1</i>.