一个细胞身份开关允许剩余的BCC存活在Hedgehog路径的抑制中
Brian Biehs1, Gerrit J P Dijkgraaf1, Robert Piskol2
1Department of Molecular Oncology, Genentech, San Francisco, CA, USA.
Nature
|October 10, 2018
概括
像vismodegib这样的刺途径抑制剂可以留下残留的基础细胞癌 (BCC) 瘤,这些瘤会重新生长. 这些残留的BCC转换为类似干细胞的身份,逃避治疗.
科学领域:
- 癌症学
- 皮肤病学
- 分子生物学
背景情况:
- 基底细胞癌 (BCC) 经常使用刺途径抑制剂治疗.
- 在停止治疗后可能会出现残留疾病和复发.
- 了解抵抗机制对于有效的BCC治疗至关重要.
研究的目的:
- 在使用Smoothened抑制剂vismodegib治疗后,研究基底细胞癌 (BCC) 瘤的行为.
- 阐明BCC治疗耐药性的细胞和分子机制.
- 确定潜在的治疗策略来克服抗药性.
主要方法:
- 使用Ptch1-Trp53基底细胞癌 (BCC) 的小鼠模型.
- 用于治疗瘤和观察到的残留疾病.
- 进行转录分析以比较残留和未经处理的BCC.
- 研究了染色体状态,Wnt路径激活,以及超级增强器重编程.
主要成果:
- 维斯莫迪吉治疗导致静止的残留BCC在药物停用后重新生长.
- 剩余的BCC采用了类似于毛囊间表皮和峡谷干细胞的转录程序.
- 这种身份交换涉及允许色素,Wnt通路激活和超级增强器重编程.
- 结合vismodegib和Wnt途径抑制剂的治疗减少了残留瘤负担并促进了分化.
结论:
- 瘤细胞可以通过采用类似干细胞的替代性来逃避vismodegib治疗.
- 这种抗药机制绕过了对原始致癌因素的依赖.
- 针对Hedgehog和Wnt途径可能提供一种提高BCC治疗效率和预防复发的策略.
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