Targeting FOXM1 condensates reduces breast tumour growth and metastasis

Area of Science:

• Molecular Biology
• Cancer Research
• Immunology

Background:

• Identifying phase-separated structures in cells is difficult, with limited intervention strategies.
• Forkhead box protein M1 (FOXM1) is implicated in cancer, but its role in phase separation is unclear.

Purpose of the Study:

• To identify phase-separated proteins in breast tumor cells.
• To investigate the role of FOXM1 in liquid-liquid phase separation (LLPS) and its impact on tumor progression.
• To explore therapeutic interventions targeting FOXM1 condensation.

Main Methods:

• Screening of phase-separated proteins in breast tumor cells.
• Utilizing an epigenetics compound library to identify suppressors of FOXM1 condensation.
• Employing a genetic code-expansion orthogonal system to study FOXM1 phosphorylation.
• Designing and testing a peptide inhibitor targeting FOXM1 LLPS.

Main Results:

• FOXM1 was identified as a key phase-separated protein in breast tumors, promoting metastasis by organizing transcription.
• AMP-activated protein kinase (AMPK) agonists were found to suppress FOXM1 condensation by phosphorylation.
• Phosphorylation disrupts FOXM1 LLPS, reduces oncogenic transcription, stimulates innate immunity, and enhances immunogenicity.
• A peptide inhibitor targeting FOXM1 LLPS effectively inhibited tumor malignancy and improved immunotherapy outcomes.

Conclusions:

• FOXM1-driven LLPS is critical for breast tumor malignancy and immune evasion.
• Targeting FOXM1 condensation with AMPK agonists or peptide inhibitors offers a promising therapeutic strategy.
• Disrupting FOXM1 LLPS can restore tumor immunogenicity and enhance immunotherapy efficacy.