DNA碎片化因子B抑制干扰素,使癌症细胞持续再生
August F Williams1, David A G Gervasio1, Claire E Turkal1
1Department of Dermatology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Nature cell biology
|November 17, 2025
概括
癌症疗法面临着阻力. 剩余的癌细胞通过抑制免疫信号而在治疗中存活下来,矛盾的是,它们使用细胞死亡途径来再生,使治疗策略复杂化.
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:
- 获得性耐药性是瘤基因向癌症治疗的一个主要挑战,导致治疗失败.
- 瘤进化和多种抗药机制使耐药癌症的治疗策略复杂化.
- 了解引发抗性的适应过程对于制定预防策略至关重要.
研究的目的:
- 研究剩余癌症持续细胞在瘤基因向治疗中生存的机制.
- 阐明药物压力诱导信号在持续细胞生长停止和逃逸中的作用.
- 确定预防获得药物耐药性的潜在目标.
主要方法:
- 对存活在瘤基因向治疗中的残留癌症持久细胞的分析.
- 研究I型干扰素信号传递在药物压力引起的生长停止中的作用.
- 利用基因操纵来评估亡机械组件 (caspases,DNA碎片化因子B,ATF3) 在持续细胞再生中的功能.
- 测量干扰素刺激基因 (ISG) 表达和持续性细胞中的DNA损伤.
主要成果:
- 剩余的癌症持久细胞是通过药物压力诱导的I型干扰素信号发送而停止的生长.
- 持久性细胞抑制干扰素刺激基因 (ISG),通过利用亡机器来逃避生长停止.
- 亚死性卡斯帕斯的参与激活了DNA碎片化因子B,导致DNA损伤和ATF3诱导.
- 由于高ISG表达,ATF3抑制ISG表达,使细胞持续再生;由于高ISG表达,缺少DNA碎片化因子B或ATF3阻止再生.
结论:
- 矛盾的是,亚致命的亡性压力促进了存活于药物治疗的残留癌细胞的再生.
- 准细胞亡途径和干扰素信号传递之间的相互作用可能为克服获得性抵抗提供策略.
- 了解持续性细胞适应机制是开发更有效和更持久的癌症疗法的关键.
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