Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation
Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation
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DOI：
10.1038/ncb2628
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发表时间：
2012-12-01
影响因子：
21.3
通讯作者：
Blanpain, Cedric
中科院分区：
文献类型：
--
作者：
Youssef, Khalil Kass;Lapouge, Gaelle;Blanpain, Cedric
基底细胞癌是人类最常见的皮肤癌，由激活Hedgehog(HH)途径突变引起；然而，从第一次致癌到侵袭性癌症发展，启动肿瘤的细胞发生了什么时间变化，人们知之甚少。使用能够在成人表皮中表达结构性活性平滑突变体(SmoM2)的可诱导小鼠模型，我们在癌症起始的不同时间对表达SmoM2的细胞进行了转录图谱分析。我们发现，启动肿瘤的细胞被大规模重新编程为类似于胚胎毛囊前体细胞(EHFP)的命运。在成人表皮中，随着SmoM2的表达，WNT/β-catenin信号被迅速激活，并与EHFP标志物的表达相一致。在表达SmoM2的成年细胞中，β-连环蛋白的缺失可以防止EHFP重新编程和肿瘤的发生。最后，人类基底细胞癌也表达Wnt信号和EHFP信号的基因。
Basal cell carcinoma, the most frequent human skin cancer, arises from activating hedgehog (HH) pathway mutations; however, little is known about the temporal changes that occur in tumour-initiating cells from the first oncogenic hit to the development of invasive cancer. Using an inducible mouse model enabling the expression of a constitutively active Smoothened mutant (SmoM2) in the adult epidermis, we carried out transcriptional profiling of SmoM2-expressing cells at different times during cancer initiation. We found that tumour-initiating cells are massively reprogrammed into a fate resembling that of embryonic hair follicle progenitors (EHFPs). Wnt/beta-catenin signalling was very rapidly activated following SmoM2 expression in adult epidermis and coincided with the expression of EHFP markers. Deletion of beta-catenin in adult SmoM2-expressing cells prevents EHFP reprogramming and tumour initiation. Finally, human basal cell carcinomas also express genes of the Wnt signalling and EHFP signatures.