A stroma-corrected ZEB1 transcriptional signature is inversely associated with antitumor immune activity in breast cancer
A stroma-corrected ZEB1 transcriptional signature is inversely associated with antitumor immune activity in breast cancer
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DOI：
10.1038/s41598-019-54282-z
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发表时间：
2019-11-28
影响因子：
4.6
通讯作者：
Wu, Guojun
中科院分区：
文献类型：
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作者：
Block, C. James;Dyson, Gregory;Wu, Guojun
上皮细胞向间质细胞转化（EMT）是一个重要的发育过程，可被癌细胞劫持，导致实验模型中转移和化疗耐药性增强。最近的研究已经将EMT相关基因签名的基因表达与多种癌症类型中增加的炎症免疫应答联系起来。然而，这些研究没有考虑到肿瘤浸润间充质基质细胞基因表达的潜在混杂效应。在这项研究中，我们全面剖析了多种EMT转录因子和EMT标志物与间质和免疫肿瘤浸润之间的关联。我们发现EMT相关基因与肿瘤内基质细胞丰度高度相关，并确定了多种癌症类型中基质校正的ZEB1表达与免疫活性降低之间的特定关系。我们推导出基质校正的ZEB1激活的转录签名，并证明该签名包括几种已知的炎症抑制剂，包括BMPR2。最后，多变量生存分析显示，ZEB1及其表达特征与乳腺癌患者总体生存率降低显著相关。总之，本研究确定了基质调节的ZEB1表达和肿瘤免疫活性之间的新关联，并解决了EMT相关基因和肿瘤间质含量之间混淆的关键问题。
The epithelial-to-mesenchymal transition (EMT) is an essential developmental process which can be hijacked by cancer cells, leading to enhanced metastasis and chemoresistance in experimental models. Recent studies have linked gene expression of EMT-associated gene signatures to increased inflammatory immune response in multiple cancer types. However, these studies did not account for the potential confounding effects of gene expression by tumor-infiltrating mesenchymal stromal cells. In this study, we comprehensively dissect the associations between multiple EMT transcription factors and EMT markers with stromal and immune tumor infiltration. We find that EMT-related genes are highly correlated with intratumoral stromal cell abundance and identify a specific relationship between stroma-corrected ZEB1 expression and decreased immune activity in multiple cancer types. We derive a stroma-corrected ZEB1-activated transcriptional signature and demonstrate that this signature includes several known inhibitors of inflammation, including BMPR2. Finally, multivariate survival analysis reveals that ZEB1 and its expression signature are significantly associated with reduced overall survival in breast cancer patients. In conclusion, this study identifies a novel association between stroma-adjusted ZEB1 expression and tumor immune activity and addresses the critical issue of confounding between EMT-associated genes and tumor stromal content.