抑制瘤微环境驱动的JAK-STAT信号增强了对三阴性乳腺癌中阿基因缺乏治疗的反应
Hila Tishler1, Shahar Ziman1, Kuoyuan Cheng2
1Department of Molecular Cell Biology, Weizmann Institute of Science, P.O. Box 26, Rehovot 76100, Israel.
Cells
|January 9, 2026
概括
瘤通过依赖瘤微环境 (TME) 来适应氨酸缺乏. 针对JAK-STAT通路与阿尔金因限制一起,有效地抑制了三阴性乳腺癌 (TNBC) 的生长.
科学领域:
- 癌症新陈代谢 癌症新陈代谢
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 氨酸酸合成酶1 (ASS1) 表达和氨酸的可用性对于瘤生长和免疫规避至关重要.
- 三阴性乳腺癌 (TNBC) 表现出代谢可塑性,影响其在瘤微环境 (TME) 内的生存.
研究的目的:
- 研究氨酸缺乏如何影响TNBC存活率及其对TME的依赖.
- 阐明TME在代谢压力下支持瘤生存的分子机制.
- 探索针对TNBC中TME介导的补偿通路的治疗策略.
主要方法:
- орто托普TNBC小鼠模型用于研究瘤代谢和TME相互作用.
- 对纤维细胞和巨细胞对瘤氨酸供应的贡献的分析.
- 对Janus酶信号传感器和转录激活器 (JAK-STAT) 信号通路激活的评估.
- 对人类TNBC数据集中的JAK-STAT基因特征与ASS1水平的相关性分析.
- 药理上抑制JAK信号传递,并与体内氨酸剥夺相结合.
主要成果:
- 缺少氨酸增加了TNBC对TME生存的依赖.
- 纤维细胞提供必要的氨酸,而巨细胞激活JAK-STAT信号,以提高瘤的存活率.
- 一个JAK-STAT基因表达特征与人类TNBC中的ASS1水平有关.
- 联合的JAK抑制和氨酸剥夺在体内显著抑制瘤生长.
结论:
- 这种TME建立了一个结构免疫电路,使得TNBC能够克服阿金缺乏.
- 针对这种TME驱动的补偿通路,特别是JAK-STAT信号,为TNBC提供了一个有前途的治疗策略.
- 诱导代谢依赖和准补偿途径可以揭示癌症治疗的可操作漏洞.
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