细胞外基质通过YAP/TEAD调节前列腺癌中的血统可塑性
Teng Han1, Zhen Sun1, Matthew Lange1
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
bioRxiv : the preprint server for biology
|January 9, 2026
概括
细胞外基质和整合素信号传递抑制神经内分泌前列腺癌 (NEPC) 的进展. 准YAP1/TEAD信号可以防止或逆转NEPC血统过渡,为前列腺腺癌 (PRAD) 提供新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
背景情况:
- 与治疗相关的神经内分泌前列腺癌 (NEPC) 是前列腺腺癌 (PRAD) 中对雄激素受体通路抑制剂 (ARPI) 治疗日益增长的耐药性机制.
- 这种血统过渡与ASCL1的上调和RB1和TP53.3的丧失有关.
- 瘤微环境在NEPC发展中的作用尚未完全理解.
研究的目的:
- 研究细胞外矩阵-整合素信号传递在调节NEPC血统过渡中的作用.
- 确定控制前列腺癌细胞可塑性的分子通路.
主要方法:
- 研究了ITGB1删除对NEPC基因表达的影响.
- 利用药理学LATS1/2抑制和构成性活跃的YAP1/TAZ突变体来调节YAP1/TEAD信号传递.
- 在前列腺腺癌和NEPC模型中分析了基因表达,转录因子细胞组 (FOXA1,TEAD) 和血统标记.
- 检查了NOTCH,AR和YAP/TEAD信号之间的相互作用.
主要成果:
- 删除ITGB1诱导的ASCL1和NE谱系基因表达,通过通过LATS1/2激活来禁用YAP1/TEAD信号.
- 恢复 YAP1/TEAD 信号阻止或逆转了 NEPC 血统过渡.
- NOTCH和AR与YAP/TEAD信号的联合抑制导致PRAD完全重新编程到NEPC.
- 血统过渡涉及FOXA1和TEAD细胞体的重新分配到NEPC特定的增强剂,这取决于FOXA1的活动.
结论:
- 细胞外矩阵/整蛋白信号传递在PRAD瘤微环境中的NEPC谱系可塑性起到制动作用.
- YAP1/TEAD信号是NEPC血统过渡的一个关键调节器.
- 针对细胞外矩阵-整合素-YAP1/TEAD信号传递,这是一种潜在的治疗策略,可以调节前列腺癌中治疗诱导的血统变化.
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