Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France.
Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France.
Cell Death Dis. 2022 Feb 2;13(2):96. doi: 10.1038/s41419-022-04538-w.
Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells' (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.
复制压力（RS）在肿瘤的发生、进展或治疗耐药中起着关键作用。在这项研究中，我们描述了乳腺癌干细胞（bCSC）对 RS 的反应及其临床意义的机制。我们在患者样本中证实，与非 bCSC 相比，bCSC 表现出有限的 RS 水平。我们首次描述了 BMI1 蛋白的空间核定位在乳腺癌中触发 RS 反应。因此，在 bCSC 中，BMI1 迅速定位于停滞的复制叉，以招募 RAD51 并激活同源重组机制，而在非 bCSC 中，BMI1 被困在去甲基化的 1q12 大片段上，从而无法有效应对 RS 反应。我们进一步证明，BMI1/RAD51 轴的激活对于预防顺铂诱导的 DNA 损伤是必要的，并且用 RAD51 抑制剂治疗患者来源的异种移植物可使肿瘤起始细胞对顺铂敏感。对 bCSC 中复制应激反应的全面了解对理解和改善治疗耐药性具有深远意义。
