A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition
A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition
复制标题
DOI：
10.1038/s41586-018-0596-y
复制
发表时间：
2018-10-18
期刊：
影响因子：
64.8
通讯作者：
de Sauvage, Frederic J.
中科院分区：
文献类型：
--
作者：
Biehs, Brian;Dijkgraaf, Gerrit J. P.;de Sauvage, Frederic J.
尽管Hedgehog通路抑制剂在治疗基底细胞癌（BCC）中有效（1），但一些患者的残留疾病仍然存在，并且可能在治疗停止时导致复发（2）。在这里，为了研究Smoothened抑制剂vismodegib对肿瘤清除的影响，我们使用了BCC 3的Ptch 1-Trp 53小鼠模型，发现用vismodegib治疗的小鼠具有静止的残留肿瘤，这些肿瘤在停止治疗后重新生长。分析实验表明，残留的BCC启动转录程序，非常类似于毛囊间表皮和峡部的干细胞，而未经处理的BCC更类似于毛囊隆起。这种细胞身份转换是通过主要允许的染色质状态实现的，伴随着快速的Wnt途径激活和超级增强子的重编程，以驱动参与细胞身份的关键转录因子的激活。因此，用维莫德吉和Wnt途径抑制剂治疗BCC减少了残余肿瘤负荷并增强了分化。我们的研究确定了一种耐药机制，其中肿瘤细胞通过采用不依赖于原始致癌驱动因子生存的替代身份来逃避治疗。
Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC)(1) , residual disease persists in some patients and may contribute to relapse when treatment is discontinued(2). Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1-Trp53 mouse model of BCC3 and found that mice treated with vismodegib harbour quiescent residual tumours that regrow upon cessation of treatment. Profiling experiments revealed that residual BCCs initiate a transcriptional program that closely resembles that of stem cells of the interfollicular epidermis and isthmus, whereas untreated BCCs are more similar to the hair follicle bulge. This cell identity switch was enabled by a mostly permissive chromatin state accompanied by rapid Wnt pathway activation and reprogramming of super enhancers to drive activation of key transcription factors involved in cellular identity. Accordingly, treatment of BCC with both vismodegib and a Wnt pathway inhibitor reduced the residual tumour burden and enhanced differentiation. Our study identifies a resistance mechanism in which tumour cells evade treatment by adopting an alternative identity that does not rely on the original oncogenic driver for survival.