Roughly half of patients with high-grade undifferentiated pleomorphic sarcoma (UPS) develop distant metastases, yet what drives that progression has remained unclear. Using spatial transcriptomics and bulk RNA-seq on paired primary and metastatic tumors, the team identified ADORA2B — an adenosine receptor already in clinical-trial development — as a key driver of UPS metastasis. CRISPR knockout and in vivo models confirmed that disabling ADORA2B halts tumor growth and spread, supporting it as a promising therapeutic target.
A new study in Clinical Cancer Research — led by Prof. Antoine Italiano (Institut Bergonié · University of Bordeaux · INSERM U1312 BRIC), with Mariella Spalato Ceruso as first author — pinpoints the adenosine A2B receptor (ADORA2B) as a critical regulator of metastatic progression in undifferentiated pleomorphic sarcoma, one of the most aggressive subtypes of soft tissue sarcoma. Explicyte contributed the spatial transcriptomic profiling, multiplex immunohistofluorescence, and bioinformatic analyses that anchored the discovery. The work was carried out in collaboration with INSERM U1312 BRIC under the CONDOR Program, with funding from Agence Nationale de la Recherche (“France 2030” / ANR-21-RHUS-0010).
To compare metastatic UPS with the primary tumors they originated from, Explicyte ran spatial transcriptomic profiling on the NanoString GeoMx Digital Spatial Profiler with the Whole Transcriptome Atlas (>18,000 protein-coding genes), on FFPE sections from three paired patients. Tumor and stromal compartments were separated using CD45 staining, giving distinct readouts for each microenvironment. Metastases showed clear upregulation of hypoxia, glycolysis, and epithelial–mesenchymal transition pathways, alongside reduced infiltration of CD8+ T cells, NK cells, and memory B cells — a coherent immune-suppressive shift. A complementary 7-plex multiplex immunohistofluorescence panel (Ventana Discovery, Akoya Opal) on a second independent cohort of five paired cases confirmed the drop in CD8+ T-cell density in metastatic lesions.
In parallel, bulk RNA-seq was performed on paired primary and metastatic samples from a separate cohort of 13 UPS patients, capturing the full transcriptomic shift at the cohort level. The analysis identified 690 differentially expressed genes and reinforced the same metastasis-associated pathways seen in the spatial data. Among the candidates overexpressed in metastases, ADORA2B was prioritized for two reasons: it has a documented role in metastatic progression across multiple epithelial cancers, and inhibitors against it are already in clinical development — making it a high-translational-potential target rather than a purely exploratory one.
Using a large institutional sarcoma database (1,432 STS primary tumors, including 330 UPS with full clinical annotation), the team confirmed ADORA2B overexpression in sarcomas relative to normal connective tissue, with the highest expression in UPS. In 199 UPS patients with disease-free survival data, ADORA2B-high tumors carried significantly shorter DFS — 61% at 5 years vs 72% in the low group (P = 0.029) — establishing ADORA2B not only as a metastasis driver but as a prognostic biomarker.
Collaborators at Institut Bergonié generated CRISPR-Cas9 ADORA2B knockouts in two patient-derived UPS cell lines (IB144, IB202). Knockout reduced proliferation, migration, and invasion in vitro, with concurrent downregulation of metalloproteases (MMP1, MMP2) involved in matrix remodeling. In orthotopic xenografts, ADORA2B-knockout tumors grew dramatically slower; in a forced-metastasis tail-vein model, the knockout arm reached 100% survival versus 0% in controls. A dual ADORA2A/ADORA2B pharmacological inhibitor (M1069), currently in early-phase clinical trials, reproduced the antiproliferative and anti-invasive effects across four UPS cell lines — confirming druggability.
ADORA2B emerges as both a metastasis driver and a prognostic biomarker in UPS — and importantly, one with inhibitors already moving through clinical trials.
For drug developers, ADORA2B inhibition is no longer just a hypothesis — it’s a target with mechanistic grounding in sarcoma biology, prognostic validation in a substantial patient cohort, and clinical-stage inhibitors already in motion. UPS, long underserved by targeted therapy, now has a credible entry point for translational work. Adenosine-axis modulators originally developed for epithelial tumors deserve evaluation in sarcoma trials — alone or combined with immune checkpoint inhibitors, particularly given the immune-suppressive signature that ADORA2B-high tumors exhibit.
