单个前列腺CTC的RNA-Seq涉及非正规的Wnt信号在抗雄激素抵抗
David T Miyamoto1, Yu Zheng2, Ben S Wittner3
1Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
概括
对前列腺癌患者循环瘤细胞 (CTC) 的单细胞分析显示出显著的异质性. 这种异质性,包括非正规的Wnt信号激活,可能解释了对雄激素受体 (AR) 抑制剂的可变反应和治疗失败.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 前列腺癌最初会对抗抗激素剥夺疗法 (ADT).
- 复发的前列腺癌通常会对雄激素受体 (AR) 抑制剂产生耐药性.
- 与骨转移活检相比,分析循环瘤细胞 (CTC) 是一种不那么侵入性的研究药物耐药性机制的方法.
研究的目的:
- 研究前列腺癌患者循环瘤细胞 (CTC) 的异质性.
- 确定对雄激素受体 (AR) 抑制剂的潜在抵抗机制.
- 探索信号通路在治疗失败中的作用.
主要方法:
- 使用微流体隔离和丰富完整的CTC.
- 通过单细胞RNA测序 (RNA-Seq) 分析了来自13名患者的77个CTC.
- 追溯分析,比较治疗和未治疗患者的CTC.
主要成果:
- 在单个CTC中观察到显著的异质性,包括AR基因突变和拼接变异.
- 在AR抑制剂进展的患者中,CTC中发现的非正规Wnt信号的激活 (P=0. 0064).
- Wnt5a过度表达降低了对AR抑制的敏感性; Wnt5a抑制恢复了对抗性细胞的部分敏感性,这在小鼠模型中得到证实.
结论:
- 对前列腺CTC单细胞分析显示信号通路存在显著的异质性.
- 异常的Wnt信号可能导致晚期前列腺癌的治疗失败.
- 了解CTC异质性对于开发抗性前列腺癌的有效治疗策略至关重要.
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