Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis

Mingming Wu(University of Science and Technology of China), Xiao Zhang(University of Science and Technology of China), Weijie Zhang(University of Science and Technology of China), Yi‐Shiou Chiou(Kaohsiung Medical University), Wenchang Qian(University of Science and Technology of China), Xiangtian Liu(University of Science and Technology of China), Min Zhang(University of Science and Technology of China), Hong Yan(University of Science and Technology of China), Shilan Li(University of Science and Technology of China), Tao Li(Anhui Medical University), Xinghua Han(University of Science and Technology of China), Pengxu Qian(First Affiliated Hospital Zhejiang University), Suling Liu(Fudan University Shanghai Cancer Center), Yueyin Pan(University of Science and Technology of China), Peter E. Lobie(Shenzhen Bay Laboratory), Tao Zhu(University of Science and Technology of China)
Nature Communications
March 16, 2022
10.1038/s41467-022-29018-9
Cited by 176Open Access
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Abstract

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 is demonstrated that the breast cancer stem cell (BCSC) secretome autonomously compresses the stem cell population. Co-implantation with BCSCs decreases the tumor-initiating capacity yet increases metastasis of accompanying cancer cells, wherein DKK1 is identified as a pivotal factor secreted by BCSCs for such functions. DKK1-promotes differentiation is indispensable for disseminated tumor cell metastatic outgrowth. In contrast, DKK1 inhibitors substantially relieve the metastatic burden by restraining metastatic cells in the dormant state. DKK1 increases the expression of SLC7A11 to protect metastasizing cancer cells from lipid peroxidation and ferroptosis. Combined treatment with a ferroptosis inducer and a DKK1 inhibitor exhibits 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.

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