Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis.
Mingming WuXiao ZhangWeijie ZhangYi-Shiou ChiouWenchang QianXiangtian LiuMin ZhangHong YanShilan LiTao LiXinghua HanPengxu QianSuling LiuYue-Yin PanPeter E LobieTao ZhuPublished in: Nature communications (2022)
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.
Keyphrases
- squamous cell carcinoma
- cancer stem cells
- small cell lung cancer
- stem cells
- cell death
- papillary thyroid
- poor prognosis
- transcription factor
- magnetic resonance
- cell therapy
- magnetic resonance imaging
- computed tomography
- cell proliferation
- signaling pathway
- molecular dynamics
- lymph node metastasis
- mesenchymal stem cells
- long non coding rna
- endoplasmic reticulum stress
- binding protein
- childhood cancer