肝内胆管癌125I粒子内放射治疗抵抗中Wnt信号通路促进肿瘤衰老细胞向肿瘤干细胞转化的机制研究

肝内胆管癌（ICC）临床缺乏满意的治疗手段，总生存期远低于肝细胞肝癌。125I粒子近距离照射治疗早期临床效果明显，远期效果不理想，治疗抵抗及肿瘤复发是主要原因。申请人及团队结合前期临床实践和基础科研的积累，立足“肿瘤干细胞”这一“罪魁祸首”，从放疗后肿瘤细胞衰老逃逸途径着手，结合前期Wnt信号通路参与ICC治疗抵抗的结果，提出科学假说：Wnt信号通路的活化促进ICC衰老细胞重编程，从而促使放疗后ICC肿瘤干细胞再生，导致ICC放疗抵抗和复发。基于此假说，本课题拟建立125I粒子治疗ICC体内外模型，研究衰老细胞重编程在ICC放疗抵抗中的关键性作用，检测ICC衰老细胞重编程后的信号通路和微环境变化，探讨Wnt信号促进ICC衰老细胞重编程的机制，寻找ICC放疗抵抗的潜在治疗靶点，最终证明通过阻断放疗后衰老细胞重编程，可抑制肿瘤干细胞新生，有效降低ICC放疗抵抗和复发，为临床转化提供依据。

Currently, the effective treatment for intrahepatic cholangiocarcinoma (ICC) remains absent, giving a much lower overall survival than does hepatocellular carcinoma. Although the short-term outcome of iodine 125 (125I) seed brachytherapy can be prominent, the long-term outcome is generally not satisfactory, mainly due to tumor resistance and recurrence. Based on our preliminary results revealing a critical role of Wnt signaling pathway in ICC therapeutic resistance, it is proposed that by activating this canonical signaling pathway can promote the reprogramming of ICC senescent cells, thereby facilitating the regeneration of cancer stem-like cells (CSCs), resulting in ICC radiotherapy resistance and recurrence. Therefore, in this study, in vivo and in vitro 125I seeds brachytherapy models were established to investigate the key role of senescent cell reprogramming in resistance to brachytherapy, changes in the signaling pathway and microenvironment after reprogramming, and mechanism of promoting reprogramming of senescent cells into CSCs, and to discover potential therapeutic targets for ICC radiotherapy resistance. The purpose of this study is to demonstrate that by blocking senescent cell reprogramming after brachytherapy can inhibit CSC regeneration and effectively reduce ICC resistance and recurrence, and is believed to provide evidence for future clinical translation and application.