High-Throughput Transcriptome Profiling of Angiosarcoma for Discovery of Novel Gene Expression Signature Associated with Chemoresistance

Angiosarcoma is a rare yet highly aggressive soft-tissue sarcoma characterized by dismal prognosis, especially in Asian patients. Treatment is notoriously challenging, with resistance to chemotherapy posing a critical challenge to angiosarcoma treatment efforts thus necessitating the discovery of biomarkers and therapeutic targets to guide precision oncology strategies. This study focuses on identifying transcriptomic biomarkers of chemoresistance in angiosarcoma. Data from 72 cases of Asian angiosarcomas were examined, including 35 cases treated with palliative chemotherapy, integrating information from Nanostring gene expression profiling, whole transcriptome profiling, immunohistochemistry, spatial transcriptomic profiling, in vitro testing, and clinicopathological data. In the chemoresistant cohort (defined as stable disease or progression), significant overexpression of genes, such as SPP1, CXCL13, CD48, and CLEC5A, was accompanied by significant enrichment of myeloid compartment as well as cytokine and chemokine signaling pathways, while the most enriched immune cell types were neutrophils and macrophages. Validation via spatial transcriptomic profiling showed SPP1 expression throughout tumor tissues, and the most enrichment in myeloid cells. Immunohistochemistry showed a significant correlation between SPP1 protein and mRNA expression, while higher SPP1 protein expression correlated with lower chemotherapeutic sensitivity in patient-derived angiosarcoma cell lines MOLAS and ISOHAS. Additionally, SPP1 mRNA overexpression is positively correlated with epithelioid histology, higher tumor grade and poorer overall survival outcomes. This study has successfully described the transcriptomic profiling of angiosarcoma for discovery of a novel gene expression signature indicative of chemoresistance and survival outcomes, thus advancing ongoing efforts for targeted therapeutic strategies for precision medicine.