TY - JOUR
T1 - Targeting ABCA12-controlled ceramide homeostasis inhibits breast cancer stem cell function and chemoresistance
AU - Cui, Jihong
AU - Christin, John R.
AU - Reisz, Julie A.
AU - Cendali, Francesca Isabelle
AU - Sanawar, Rahul
AU - De Miranda, Marcelo Coutinho
AU - D'Alessandro, Angelo
AU - Guo, Wenjun
N1 - Publisher Copyright:
© 2023 American Association for the Advancement of Science. All rights reserved.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85178363749&partnerID=8YFLogxK
U2 - 10.1126/SCIADV.ADH1891
DO - 10.1126/SCIADV.ADH1891
M3 - Article
C2 - 38039374
AN - SCOPUS:85178363749
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 48
M1 - eadh1891
ER -