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ABCA12-mediated ceramide efflux governs breast cancer stem cell function

ABSTRACT: Cancer stem cells (CSCs) drive tumor growth, metastasis, relapse, and chemoresistance. However, it’s unclear how lipid metabolism, especially sphingolipids metabolism, regulates CSCs and chemoresistance. In this study, we developed spontaneous tumor models expressing a Sox9-GFP transgenic reporter and demonstrated that cancer cells expressing high levels of SOX9 functioned as CSCs in both primary tumors and metastases. Transcriptomics analyses uncovered that SOX9high CSCs upregulate ABCA12 lipid transporter. Functionally, downregulation of ABCA12 impaired cancer stemness and chemoresistance of SOX9high cells. Through lipidomic analysis, we demonstrated that ABCA12 regulates SOX9 expression and cancer stemness by controlling ceramide abundance. Blocking ceramide hydrolysis using acid ceramidase inhibitor D-NMAPPD sensitized tumors to chemotherapy and prevented enrichment of SOX9high CSCs. These data suggest a potential strategy for targeting CSCs and overcoming chemoresistance. We further demonstrated that ceramide inhibits the YAP/TAZ signaling that is required for SOX9 expression in breast CSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE220178 | GEO | 2023/11/01

REPOSITORIES: GEO

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