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

Author

Listed:
  • Mingming Wu

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Xiao Zhang

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Weijie Zhang

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Yi Shiou Chiou

    (Tsinghua Shenzhen International Graduate School
    Kaohsiung Medical University
    Shenzhen Bay Laboratory)

  • Wenchang Qian

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Xiangtian Liu

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Min Zhang

    (University of Science and Technology of China
    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

    (The First Affiliated Hospital of Anhui Medical University)

  • Xinghua Han

    (University of Science and Technology of China)

  • Pengxu Qian

    (Zhejiang University School of Medicine, Hangzhou)

  • Suling Liu

    (Fudan University)

  • Yueyin Pan

    (University of Science and Technology of China)

  • Peter E. Lobie

    (Tsinghua Shenzhen International Graduate School
    Shenzhen Bay Laboratory)

  • Tao Zhu

    (University of Science and Technology of China
    University of Science and Technology of China)

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.

Suggested Citation

  • Mingming Wu & Xiao Zhang & Weijie Zhang & Yi Shiou Chiou & Wenchang Qian & Xiangtian Liu & Min Zhang & Hong Yan & Shilan Li & Tao Li & Xinghua Han & Pengxu Qian & Suling Liu & Yueyin Pan & Peter E. Lo, 2022. "Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29018-9
    DOI: 10.1038/s41467-022-29018-9
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    1. Jiawen Bu & Yixiao Zhang & Sijin Wu & Haonan Li & Lisha Sun & Yang Liu & Xudong Zhu & Xinbo Qiao & Qingtian Ma & Chao Liu & Nan Niu & Jinqi Xue & Guanglei Chen & Yongliang Yang & Caigang Liu, 2023. "KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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