通过激活AKT和YAP信号调节的独特分子通路在肝脏内胆管癌进展期间:AKT和YAP在iCCA期间的作用
Jinqiu Zhao1, Lian Yang2, Yujia Qin3
1Department of Infectious Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Western Institute of Digital-Intelligent Medicine, Chongqing 401329, China; Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
这项研究揭示了AKT和YAP在肝内胆管癌 (iCCA) 进展中的不同作用. YAP抑制重塑了瘤免疫微环境,支持用于iCCA治疗的免疫检查点抑制剂的组合疗法.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 激活的AKT和YAP信号与肝脏内胆管癌 (iCCA) 病原发生有关.
- 它们在瘤进展和瘤微环境 (TME) 中的确切作用尚未完全理解.
研究的目的:
- 阐明AKT和YAP信号在iCCA进展和TME监管中的不同角色.
- 评估针对这些途径的治疗潜力,单独或与免疫检查点抑制剂结合使用.
主要方法:
- 开发了两种可诱导多西环素iCCA小鼠模型 (Akt/TRE-YAP和TRE-Akt/YAP) 用于选择性途径抑制.
- 组织学和分子分析,以评估表型变化和途径调节在多西环林撤销后.
- 在人类iCCA样本中验证发现.
主要成果:
- AKT抑制导致了显著的iCCA回归,而YAP抑制最初导致了回归,但后来转变为稳定性-HCC.
- AKT调节瘤细胞增殖和新陈代谢;YAP通过抑制瘤抑制剂RNF125.5来调节增殖,分化和免疫微环境.
- 抑制YAP降低了中性粒细胞的数量,并增加了CD4+/CD8+ T细胞的透,但这些T细胞表达了PD-1.
- 结合YAP抑制和抗PD-L1治疗导致了严重的瘤回归.
结论:
- 在iCCA进展中,AKT和YAP的显著分子特征得到了特征.
- YAP被确定为瘤免疫微环境 (TIME) 的关键调节者.
- 对YAP抑制与免疫检查点抑制剂 (ICI) 的联合治疗显示出对iCCA治疗的强烈临床前前景.
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