小柯机器人

日本庆应大学医学院Toshiro Sato研究组发现，细胞-基质界面调控人类结肠癌干细胞的休眠状态。2022年7月7日，《自然》杂志在线发表了这项成果。

研究人员开发了一个活体基因系追踪系统，可以纵向追踪异种移植的人类结直肠癌类器官中的单个细胞，并确定在未经化疗状态下显示休眠行为的LGR5⁺癌症干细胞（CSC）。休眠期的LGR5⁺细胞以p27表达为标志，活体成像直接显示了LGR5⁺p27⁺细胞在化疗期间的持续存在，随后是克隆扩张。转录组分析显示，在休眠期的LGR5⁺p27⁺细胞中，COL17A1（一种加强hemidesmosome的细胞粘附分子）的上调。

COL17A1敲除的类器官失去了休眠的LGR5⁺p27⁺亚群，并对化疗变得敏感，这表明细胞-基质界面在休眠维持中的作用。化疗破坏了COL17A1，并通过FAK-YAP的激活打破了LGR5⁺p27⁺细胞的休眠状态。废除YAP信号抑制了耐化疗细胞退出休眠期，并延迟了肿瘤的重新生长，这突出了YAP抑制在防止癌症复发方面的治疗潜力。这些结果为克服人类结直肠癌对传统化疗的抗拒性提供了一种可行的治疗方法。

据介绍，化疗后癌症复发仍然是癌症相关死亡的主要原因。虽然复发被认为是由于驻留的CSC增殖所致，但由于缺乏能够以足够时空分辨率对CSC动态进行前瞻性分析的实验平台，阻碍了对这一假设的测试。

附：英文原文

Title: Cell-matrix interface regulates dormancy in human colon cancer stem cells

Author: Ohta, Yuki, Fujii, Masayuki, Takahashi, Sirirat, Takano, Ai, Nanki, Kosaku, Matano, Mami, Hanyu, Hikaru, Saito, Megumu, Shimokawa, Mariko, Nishikori, Shingo, Hatano, Yoshiko, Ishii, Ryota, Sawada, Kazuaki, Machinaga, Akihito, Ikeda, Wataru, Imamura, Takeshi, Sato, Toshiro

Issue&Volume: 2022-07-07

Abstract: 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 (CSCs)1, a lack of experimental platforms that enable prospective analysis of CSC dynamics with sufficient spatiotemporal resolution has hindered testing of this hypothesis. Here, we develop a live genetic lineage-tracing system that allows longitudinal tracking of individual cells in xenotransplanted human colorectal cancer organoids and identify LGR5+ CSCs that display a dormant behavior in a chemo-naive state. Dormant LGR5+ cells are marked by p27 expression, and intravital imaging directly demonstrates the persistence of LGR5+p27+ cells during chemotherapy, followed by clonal expansion. Transcriptome analysis reveals an upregulation of COL17A1, a cell adhesion molecule that strengthens hemidesmosome, in dormant LGR5+p27+ cells. COL17A1-knockout organoids lose the dormant LGR5+p27+ subpopulation and become sensitive to chemotherapy, suggesting a role of cell-matrix interface in dormancy maintenance. Chemotherapy disrupts COL17A1 and breaks the dormancy in LGR5+p27+ cells through FAK-YAP activation. Abrogation of YAP signaling restrains chemo-resistant cells from exiting dormancy and delays tumor regrowth, highlighting the therapeutic potential of YAP inhibition in preventing cancer relapse. These results offer a viable therapeutic approach to overcome refractoriness of human colorectal cancer to conventional chemotherapy.

DOI: 10.1038/s41586-022-05043-y

Source: https://www.nature.com/articles/s41586-022-05043-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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