Cell-matrix interface regulates dormancy in human colon cancer stem cells
Cell-matrix interface regulates dormancy in human colon cancer stem cells
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DOI：
10.1038/s41586-022-05043-y
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发表时间：
2022-07-07
期刊：
影响因子：
64.8
通讯作者：
Sato, Toshiro
中科院分区：
文献类型：
--
作者：
Ohta, Yuki;Fujii, Masayuki;Sato, Toshiro
化疗后癌症复发仍然是癌症相关死亡的主要原因。尽管复发被认为是由常驻癌症干细胞的繁殖引起的（1），但缺乏能够以足够的时空分辨率对癌症干细胞动力学进行前瞻性分析的实验平台阻碍了这一假设的检验。在这里，我们开发了一种活的遗传谱系追踪系统，可以纵向追踪异种移植的人结直肠癌类器官中的单个细胞，并鉴定出在化疗初始状态下表现出休眠行为的LGR 5（+）癌症干细胞。背角LGR 5（+）细胞以p27的表达为标志，活体成像提供了化疗期间LGR 5（+）p27（+）细胞持续存在的直接证据，随后是克隆扩增。转录组分析显示，COL 17 A1-一种强化半桥粒的细胞粘附分子-在休眠的LGR 5（+）p27（+）细胞中上调。其中COL 17 A1被敲除的类器官失去了休眠的LGR 5（+）p27（+）亚群，并且变得对化疗敏感，这表明细胞-基质界面在休眠的维持中起作用。化疗通过FAK-YAP激活破坏COL 17 A1并打破LGR 5（+）p27（+）细胞的休眠。消除雅普信号传导可防止化学抗性细胞退出休眠并延迟肿瘤的再生长，突出了雅普抑制在预防癌症复发方面的治疗潜力。这些结果提供了一种可行的治疗方法，以克服人类结直肠癌的传统化疗的难治性。
Cancer relapse after chemotherapy remains a main cause of cancer-related death. Although the relapse is thought to result from the propagation of resident cancer stem cells(1), a lack of experimental platforms that enable the prospective analysis of cancer stem cell dynamics with sufficient spatiotemporal resolution has hindered the testing of this hypothesis. Here we develop a live genetic lineage-tracing system that allows the longitudinal tracking of individual cells in xenotransplanted human colorectal cancer organoids, and identify LGR5(+) cancer stem cells that exhibit a dormant behaviour in a chemo-naive state. Dormant LGR5(+) cells are marked by the expression of p27, and intravital imaging provides direct evidence of the persistence of LGR5(+)p27(+) cells during chemotherapy, followed by clonal expansion. Transcriptome analysis reveals that COL17A1-a cell-adhesion molecule that strengthens hemidesmosomes-is upregulated in dormant LGR5(+)p27(+) cells. Organoids in which COL17A1 is knocked out lose the dormant LGR5(+)p27(+) subpopulation and become sensitive to chemotherapy, which suggests that the cell-matrix interface has a role in the maintenance of dormancy. Chemotherapy disrupts COL17A1 and breaks the dormancy in LGR5(+)p27(+) cells through FAK-YAP activation. Abrogation of YAP signalling prevents chemoresistant cells from exiting dormancy and delays the regrowth of tumours, highlighting the therapeutic potential of YAP inhibition in preventing cancer relapse. These results offer a viable therapeutic approach to overcome the refractoriness of human colorectal cancer to conventional chemotherapy.