Targeting the oncogenic TBX3:nucleolin complex to treat multiple sarcoma subtypes.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Sarcomas are challenging cancers due to limited biomarkers and treatments.
• The transcription factor TBX3 is implicated in various sarcoma subtypes, presenting a potential therapeutic target.

Purpose of the Study:

• To identify cofactors regulating TBX3's oncogenic role in sarcomas.
• To investigate the therapeutic potential of targeting the TBX3-nucleolin interaction.

Main Methods:

• Affinity purification coupled with mass spectrometry to identify TBX3 cofactors.
• Co-expression analysis and interaction studies in sarcoma cell lines.
• Assessment of aptamer AS1411's anti-cancer activity and mechanism of action.

Main Results:

• Nucleolin was identified as a TBX3 cofactor, co-expressed with TBX3 in sarcoma patients, correlating with poor prognosis.
• TBX3 and nucleolin interact in chondrosarcoma, liposarcoma, and rhabdomyosarcoma cells, promoting proliferation and migration.
• The aptamer AS1411 selectively targeted cancer cells, disrupted the TBX3-nucleolin interaction, and re-expressed tumor suppressors CDKN1A and CDKN2A.

Conclusions:

• Nucleolin is essential for TBX3's oncogenic activity in sarcomagenesis.
• Disrupting the TBX3-nucleolin interaction with AS1411 represents a novel therapeutic strategy for sarcomas.