Nakano Kiyotaka, Oki Eiji, Yamazaki Masaki, Suzuki Masami, Kawai Shigeto, Fujita Takanori, Kato Atsuhiko, Zaitsu Yoko, Jogo Tomoko, Kato Chie, Watanabe Takeshi, Hashimoto Eri, Nishime Chiyoko, Fujii Etsuko, Ando Koji, Nagae Genta, Harimoto Norifumi, Ota Mitsuhiko, Saeki Hiroshi, Aburatani Hiroyuki, Maehara Yoshihiko, Yamazaki Tatsumi
Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan.
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan.
Cell Death Discov. 2025 Jun 20;11(1):282. doi: 10.1038/s41420-025-02567-w.
The effectiveness of colorectal cancer (CRC) therapy is limited owing to the absence of treatments targeting drug-tolerant residual cancer cells. Although neoadjuvant therapy is effective, pathological examination of residual tumors has revealed the presence of small clusters of LGR5-positive cancer cells in the fibrous tissue. Here, we established a colorectal cancer cell line-derived organoid (CCD-organoid) regrowth model using a patient-derived cell line with cancer stem cell properties and demonstrated that it displayed the morphological characteristics of small clusters in clinical tissues. Time course analysis of single-cell RNA sequencing of the CCD-organoid regrowth model revealed various states and dynamic alterations within non-cycling cells. We identified subpopulations highly expressing protein translation-related genes RPL17 and EEF1G. To identify key signals for the transition of residual cancer cells to regrowth, we evaluated inhibitors targeting pathways such as the Wnt pathway, reactive oxygen species pathway, and RNA polymerase I pathway, highlighted in the single-cell RNA sequencing analysis. Only the polymerase I-inhibitor BMH-21 significantly reduced tumor growth both in vitro and in vivo, indicating the critical cell subpopulation driving recurrence. Our results demonstrate the possibility of a unique therapeutic target for CRC treatment targeting drug-tolerant residual cancer cells.
由于缺乏针对耐药残留癌细胞的治疗方法，结直肠癌（CRC）治疗的效果有限。尽管新辅助治疗有效，但对残留肿瘤的病理检查显示，在纤维组织中存在小簇LGR5阳性癌细胞。在这里，我们使用具有癌症干细胞特性的患者来源细胞系建立了结直肠癌细胞系来源的类器官（CCD-类器官）再生模型，并证明它展现出临床组织中小簇的形态特征。对CCD-类器官再生模型进行单细胞RNA测序的时间进程分析揭示了非循环细胞内的各种状态和动态变化。我们鉴定出了高表达蛋白质翻译相关基因RPL17和EEF1G的亚群。为了确定残留癌细胞向再生转变的关键信号，我们评估了针对单细胞RNA测序分析中突出显示的Wnt通路、活性氧通路和RNA聚合酶I通路等途径的抑制剂。只有聚合酶I抑制剂BMH-21在体外和体内均显著降低了肿瘤生长，表明驱动复发的关键细胞亚群。我们的结果证明了针对耐药残留癌细胞的CRC治疗具有独特治疗靶点的可能性。
