ACSS2 Suppresses Ferroptosis to Drive Breast Cancer Brain Metastasis

Area of Science:

• Oncology
• Metabolic pathways
• Cancer metastasis

Background:

• Brain metastasis in breast cancer is a terminal stage with poor prognosis.
• Tumor cells must adapt to the brain's microenvironment, including high acetate levels.
• Acetate metabolism to acetyl-CoA, via acetyl-CoA synthetase 2 (ACSS2), is crucial for brain tumor cells.

Purpose of the Study:

• To investigate the role of ACSS2 and its regulation in breast cancer brain metastasis.
• To explore ACSS2 as a therapeutic target for brain metastatic breast cancer.

Main Methods:

• Compared O-GlcNAc, O-GlcNAc transferase (OGT), and phosphorylated ACSS2 (pACSS2) levels in brain-metastatic vs. parental breast cancer cells.
• Assessed the necessity of OGT and CDK5 for in vivo brain tumor growth.
• Utilized a phospho-mimetic S267D ACSS2 mutant to study its effect on brain metastatic progression.
• Investigated the mechanism of ACSS2-mediated ferroptosis suppression via SLC7A11 and E2F1.
• Evaluated the efficacy of the ACSS2 inhibitor AD-5584 in ex vivo and in vivo models.

Main Results:

• Brain-metastatic breast cancer cells showed increased O-GlcNAc, OGT, and pACSS2 (Ser267).
• OGT and CDK5 were essential for tumor growth in the brain.
• ACSS2 and S267D mutant promoted brain metastatic breast cancer progression.
• ACSS2 suppressed ferroptosis by upregulating SLC7A11 through E2F1.
• AD-5584 treatment induced ferroptosis and inhibited tumor growth.

Conclusions:

• ACSS2 is a key metabolic regulator in breast cancer brain metastasis.
• Targeting ACSS2 with inhibitors like AD-5584 can induce ferroptosis and suppress tumor growth.
• ACSS2 represents a promising therapeutic target for treating breast cancer brain metastases.