Targeting ABCA12-controlled ceramide homeostasis inhibits breast cancer stem cell function and chemoresistance
Menée à l'aide de lignées cellulaires, d'organoïdes, de modèles murins et de xénogreffes dérivées de tumeurs de patients, cette étude met en évidence l'intérêt de réduire l'expression du transporteur lipidique ABCA12 pour favoriser l'accumulation des céramides dans les cellules souches cancéreuses et sensibiliser ces dernières à la chimiothérapie
Cancer stem cells (CSCs) drive tumor growth, metastasis, and chemoresistance. While emerging evidence suggests that CSCs have a unique dependency on lipid metabolism, the functions and regulation of distinct lipid species in CSCs remain poorly understood. Here, we developed a stem cell factor SOX9-based reporter for isolating CSCs in primary tumors and metastases of spontaneous mammary tumor models. Transcriptomic analyses uncover that SOX9high CSCs up-regulate the ABCA12 lipid transporter. ABCA12 down-regulation impairs cancer stemness and chemoresistance. Lipidomic analyses reveal that ABCA12 maintains cancer stemness and chemoresistance by reducing intracellular ceramide abundance, identifying a CSC-associated function of ABCA subfamily transporter. Ceramide suppresses cancer stemness by inhibiting the YAP-SOX9 signaling pathway in CSCs. Increasing ceramide levels in tumors enhances their sensitivity to chemotherapy and prevents the enrichment of SOX9high CSCs. In addition, SOX9high and ABCA12high cancer cells contribute to chemoresistance in human patient-derived xenografts. These findings identify a CSC-suppressing lipid metabolism pathway that can be exploited to inhibit CSCs and overcome chemoresistance. CSCs maintain stemness and enhance chemoresistance via the ABCA12-mediated expulsion of ceramide lipids that inhibit YAP-SOX9.