2. Academic Validation
  3. Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis

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

  • Nat Commun. 2022 Mar 16;13(1):1371. doi: 10.1038/s41467-022-29018-9.
Mingming Wu # 1 2,  Xiao Zhang # 1 2,  Weijie Zhang 1 2,  Yi Shiou Chiou 3 4 5,  Wenchang Qian 1 2,  Xiangtian Liu 1 2,  Min Zhang 1 2,  Hong Yan 6,  Shilan Li 6,  Tao Li 7,  Xinghua Han 1,  Pengxu Qian 8,  Suling Liu 9,  Yueyin Pan 1,  Peter E Lobie 10 11,  Tao Zhu 12 13
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 2 The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 3 Tsinghua-Berkeley Shenzhen Institute and Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, China.
  • 4 Master Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 5 Shenzhen Bay Laboratory, Shenzhen, China.
  • 6 Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 7 Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 8 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences and Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 9 Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institute, Fudan University, Shanghai, China.
  • 10 Tsinghua-Berkeley Shenzhen Institute and Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, China. pelobie@sz.tsinghua.edu.cn.
  • 11 Shenzhen Bay Laboratory, Shenzhen, China. pelobie@sz.tsinghua.edu.cn.
  • 12 The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. zhut@ustc.edu.cn.
  • 13 The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. zhut@ustc.edu.cn.
  • # Contributed equally.
PMID: 35296660 DOI: 10.1038/s41467-022-29018-9
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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