Cancer Stem Cell Regulated Phenotypic Plasticity Protects Metastasized Cancer Cells from Ferroptosis

Cancer cells display phenotypic equilibrium between the stem-like and differentiated states during neoplastic homeostasis. The functional and mechanistic implications of this subpopulation plasticity remain largely unknown. Herein, it was demonstrated that the breast cancer stem cell (BCSC) secretome autonomously compressed the stem cell population. Co-implantation with BCSCs decreased the tumor-initiating capacity yet increased metastasis of accompanying cancer cells, wherein DKK1 was identified as a pivotal factor secreted by BCSCs for such functions. DKK1-promoted differentiation was indispensable for disseminated tumor cell metastatic outgrowth. In contrast, DKK1 inhibitors substantially relieved the metastatic burden by restraining metastatic cells in the dormant state. DKK1 increased the expression of SLC7A11 to protect metastasizing cancer cells from lipid peroxidation and ferroptosis. Combined treatment with ferroptosis inducer and DKK1 inhibitor exhibited synergistic effects in diminishing metastasis. Hence, this study deciphers the contribution of CSC-regulated phenotypic plasticity in metastatic colonization and provides therapeutic approaches to limit metastatic outgrowth.