Adenosine A2B Receptor Promotes Tumor Progression and Metastases in Undifferentiated Pleomorphic Sarcoma

PURPOSE: Undifferentiated pleomorphic sarcoma (UPS) is an aggressive subtype of soft tissue sarcoma with poor outcomes, particularly in metastatic cases. The mechanisms driving metastasis in UPS remain poorly understood, limiting therapeutic advances. EXPERIMENTAL DESIGN: A multi-omics approach was used to analyze paired primary and metastatic UPS tumor samples. Spatial transcriptomics, bulk RNA sequencing, and deconvolution analyses were performed to identify molecular pathways and immune microenvironment alterations associated with metastasis. Functional assays using CRISPR-Cas9 knockout (KO) UPS cell lines, alongside in vivo models, were used for functional validation experiments. RESULTS: Transcriptomic analyses on 13 patients with UPS revealed significant upregulation of hypoxia, epithelial-mesenchymal transition, and immune-suppressive pathways in metastatic UPS. ADORA2B was identified as a key driver of these processes, with elevated expression correlating with poor disease-free survival in patients with UPS. Functional studies confirmed that ADORA2B promotes proliferation, migration, invasion, and matrix remodeling via metalloprotease regulation. In vivo, ADORA2B KO reduced primary tumor growth and metastatic dissemination in UPS models. CONCLUSIONS: This study identifies ADORA2B as a critical regulator of metastatic progression in UPS, implicating it as a promising therapeutic target. Ongoing clinical trials targeting adenosine pathways further support the translational potential of ADORA2B inhibition to disrupt metastasis and improve outcomes for patients with UPS.