结肠直肠癌有机模型揭示了在单细胞分辨率下对氨酸抗性的机制
Yi Pan1,2, Lin Chen1,2, Yuqing Hu1,2
1Central Laboratory and Precision Medicine Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China.
Cancer medicine
|February 12, 2026
概括
结肠直肠癌中虹素耐药性是由Wnt信号传递和脂质代谢-Notch通路驱动的. 患者衍生器官和单细胞测序确定了特定的细胞群作为克服治疗失败的潜在治疗标.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 基因组学就是基因组学.
背景情况:
- 转移性结肠直肠癌 (mCRC) 治疗用氨酸面临显著的耐药性,影响患者的结果.
- 大约30%-50%的mCRC患者经历了治疗失败,原因是耐氨酸剂的耐药性.
- 了解氨酸耐药性的分子基础对于开发有效疗法至关重要.
研究的目的:
- 系统地阐明结肠直肠癌 (CRC) 中的氨基酸耐药性分子机制.
- 为了利用患者衍生的有机体 (PDO) 模型和单细胞转录组学来获得机械洞察力.
- 为了确定克服耐氨酸抗性的新疗法标.
主要方法:
- 已建立的PDO模型来自耐氨酸和敏感的CRC患者.
- 在12360个细胞上进行单细胞RNA测序 (scRNA-seq),以分析转录组异质性.
- 采用基因组变异分析 (GSVA),转录性调节网络和细胞通信网络.
主要成果:
- 在PDO模型中确认了与临床表型相关的独特药物敏感性概况.
- 通过scRNA-seq.识别了CRC5特异性耐药细胞集群 (集群1和集群6).
- 集群1显示激活Wnt信号和ECM重塑;集群6显示丰富的脂质代谢和Notch信号.
结论:
- 集成的PDO模型和scRNA-seq以揭示驱动类固醇耐药性的关键亚群.
- 确定了Wnt信号激活和脂质代谢-Notch通路协同作用作为核心阻力机制.
- 突出了集群1 (MARCKSL1+) 和集群6 (AKR1C3+) 作为组合疗法的潜在治疗点.
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