A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours
A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours
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基质成纤维细胞中的ZEB1/p53信号轴促进乳腺上皮肿瘤
DOI：
10.1038/s41467-019-11278-7
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发表时间：
2019-07-19
影响因子：
16.6
通讯作者：
Wu, Zhao-Qiu
中科院分区：
文献类型：
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作者：
Fu, Rong;Han, Chen-Feng;Wu, Zhao-Qiu
越来越多的证据表明，锌指转录因子ZEB 1主要表达在几种肿瘤的基质中。然而，间质ZEB 1在肿瘤进展中的作用仍未探索。在这项研究中，在查询人类数据库的同时，我们发现在间质中表达高水平ZEB 1的乳腺癌患者的无复发生存率显著降低。使用小鼠乳腺癌模型，我们发现间质成纤维细胞中的ZEB 1失活抑制肿瘤的发生、发展和转移。我们认为这与细胞外基质重塑减少、免疫细胞浸润和血管生成减少有关。基质成纤维细胞中ZEB 1缺失增加了乙酰化、表达和p53向FGF 2/7、VEGF和IL 6启动子的募集，从而减少了它们的产生和分泌到周围基质中。重要的是，ZEB 1基质缺失乳腺肿瘤中的p53消融足以恢复受损的癌症生长和进展。我们的研究结果将ZEB 1/p53轴确定为促进乳腺上皮肿瘤的基质特异性信号通路。
Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing highZEB1levels in the stroma. Using a mouse model of breast cancer, we show thatZEB1inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis.ZEB1deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 toFGF2/7,VEGFandIL6promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly,p53ablation inZEB1stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.