JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance

SUMMARY

Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B ( CPT1B), which encodes the critical enzyme for fatty acid β-oxidation (FAO). Moreover, mammary adipocyte-derived leptin upregulates STAT3-induced CPT1B expression and FAO activity in BCSCs. Human breast cancer-derived data suggest STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking FAO and/or leptin re-sensitizes them to chemotherapy and inhibits BCSCs in mouse breast tumors in vivo. We identify a critical pathway for BCSC maintenance and breast cancer chemoresistance.

eTOC

Cancer stem cells play an important role in cancer development and chemoresistance. Wang et al. show that leptin-JAK/STAT3 regulates lipid metabolism through fatty acid β-oxidation (FAO), promoting breast cancer stemness and chemoresistance. Blocking FAO and/or depleting leptin re-sensitize cancer cells to chemotherapy while reducing cancer stemness in vivo.