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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Undifferentiated pleomorphic sarcoma (UPS) is an aggressive soft tissue sarcoma with poor prognosis, especially in metastatic stages.
• The molecular mechanisms underlying UPS metastasis are not well understood, hindering the development of effective treatments.

Purpose of the Study:

• To investigate the molecular drivers of metastasis in undifferentiated pleomorphic sarcoma (UPS).
• To identify potential therapeutic targets for inhibiting UPS metastasis and improving patient outcomes.

Main Methods:

• Employed a multi-omics approach, including spatial transcriptomics and bulk RNA sequencing, on paired primary and metastatic UPS tumors.
• Utilized CRISPR-Cas9 gene editing in UPS cell lines and in vivo models for functional validation of identified pathways.
• Performed deconvolution analyses to assess alterations in the tumor immune microenvironment associated with metastasis.

Main Results:

• Identified significant upregulation of hypoxia, epithelial-mesenchymal transition (EMT), and immune-suppressive pathways in metastatic UPS.
• ADORA2B was identified as a key driver, with its elevated expression correlating with reduced disease-free survival in UPS patients.
• Functional studies demonstrated that ADORA2B promotes tumor cell proliferation, migration, invasion, and matrix remodeling; in vivo, ADORA2B knockout reduced tumor growth and metastasis.

Conclusions:

• ADORA2B is a critical regulator of metastatic progression in undifferentiated pleomorphic sarcoma (UPS).
• ADORA2B represents a promising therapeutic target for disrupting metastasis in UPS.
• The findings support ongoing clinical trials targeting adenosine pathways for potential treatment of UPS.