Tumor therapeutics often target the primary tumor bulk but fail to eradicate therapy-resistant cancer stem cells (CSCs) in quiescent state. These can then become activated to initiate recurrence and/or metastasis beyond therapy. Here, we identified and isolated chemoradiotherapy-resistant CSCs in quiescent state with high capacity of tumor-initiation and tumorsphere formation from three types of breast tumors in mice. Experiments of knockdown and rescue revealed DEK, a nuclear protein, as essential for CSC activation. Exogenous DEK was then used to trigger quiescence exit of CSCs. ChIP-seq and ATAC-seq showed that DEK directly binds to chromatin, facilitating its genome-wide accessibility. The resulting epigenetic events upregulate the expression of cellular activation-related genes including MYC targets, whereas cellular quiescence-related genes including the p53 signaling pathway are silenced. However, twinned with DEK-induced activation, formerly resistant CSCs were then destroyed by chemotherapy in vitro. In mice, traditional chemoradiotherapy concurrent with the injection of DEK-containing exosomes resulted in eradication of primary tumors together with formerly resistant CSCs without recurrence or metastasis. Our findings advance knowledge of the mechanism of quiescent CSC activation and may provide novel clinical opportunities for removal of quiescence-linked therapy resistance.
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We thank Xing-hui Song of the core facilities, Zhejiang University school of medicine, for assistance with fluorescence-activated cell and exosome sorting.
This work was supported by the National Major Research and Development Project (2016YFA0101201) and the National Natural Science Foundation of China (Project No. 31730084).
The authors declare no competing interests.
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Yang, YS., Jia, XZ., Lu, QY. et al. Exosomal DEK removes chemoradiotherapy resistance by triggering quiescence exit of breast cancer stem cells. Oncogene 41, 2624–2637 (2022). https://doi.org/10.1038/s41388-022-02278-x