Targeting ABCA12-controlled ceramide homeostasis inhibits breast cancer stem cell function and chemoresistance

Area of Science:

• Oncology
• Cancer Biology
• Lipid Metabolism

Background:

• Cancer stem cells (CSCs) are crucial drivers of tumor progression, metastasis, and treatment resistance.
• The specific roles and regulation of lipid metabolism in CSCs are not well understood.
• CSCs exhibit unique dependencies on lipid metabolism for their survival and function.

Purpose of the Study:

• To investigate the role of lipid metabolism in cancer stem cell function and chemoresistance.
• To identify novel therapeutic targets for inhibiting CSCs and overcoming chemoresistance.
• To elucidate the signaling pathways regulated by specific lipids in CSCs.

Main Methods:

• Development of a SOX9-based reporter for CSC isolation from mammary tumor models.
• Transcriptomic and lipidomic analyses of SOX9-high CSCs.
• Functional studies involving ABCA12 down-regulation and ceramide level manipulation.
• Assessment of CSC enrichment and chemoresistance in patient-derived xenografts.

Main Results:

• SOX9-high CSCs up-regulate the lipid transporter ABCA12.
• ABCA12 down-regulation reduces CSC stemness and chemoresistance.
• ABCA12 maintains CSCs by decreasing intracellular ceramide levels.
• Ceramide suppresses CSC stemness via the YAP-SOX9 signaling pathway.
• Elevated ceramide enhances chemotherapy sensitivity and reduces CSC enrichment.
• SOX9-high and ABCA12-high cells contribute to chemoresistance in human xenografts.

Conclusions:

• A novel CSC-suppressing lipid metabolism pathway involving ABCA12 and ceramide has been identified.
• Targeting this pathway, specifically by increasing ceramide levels, can inhibit CSCs.
• This approach holds potential for overcoming chemoresistance in various cancers.