Chromosome instability drives phenotypic switching to metastasis
Chromosome instability drives phenotypic switching to metastasis
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DOI：
10.1073/pnas.1618215113
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发表时间：
2016-12-20
影响因子：
11.1
通讯作者：
Woude, George F. Vande
中科院分区：
文献类型：
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作者：
Gao, ChongFeng;Su, Yanli;Woude, George F. Vande
染色体不稳定性（CIN）是人类癌症最显着的特征。然而，CIN 如何驱动肿瘤进展至转移仍不清楚。在这里，我们研究了染色体含量变化在产生转移所需的表型动态方面的作用。我们从人类癌细胞系中分离出上皮和间质克隆，并表明上皮克隆能够产生间质变体，这有可能进一步自主产生上皮回复体。侵袭性间充质和上皮表型的连续获得概括了肿瘤进展到转移的步骤。重要的是，克隆上皮群体产生的间充质变体与染色体含量的细微变化有关，这改变了染色体转录组并影响编码细胞间连接（IJ）蛋白的基因的表达，而在间充质克隆产生的上皮变体中经常检测到含有ZEB1基因的10p染色体丢失。敲低上皮细胞中的这些 IJ 基因会诱导间充质表型，而敲低间充质细胞中的 ZEB1 基因会诱导上皮表型，这证明了染色体含量变化在表型决定中的因果作用。因此，我们的研究提出了肿瘤转移的范例：失去携带 IJ 基因的染色体的原发性上皮癌细胞获得侵袭性间充质表型，随后的染色体内容变化（例如播散性间充质细胞中 10p 的丢失）产生上皮变体，这些变体可以在转移定植期间被选择产生上皮肿瘤。
Chromosome instability (CIN) is the most striking feature of human cancers. However, how CIN drives tumor progression to metastasis remains elusive. Here we studied the role of chromosome content changes in generating the phenotypic dynamics that are required for metastasis. We isolated epithelial and mesenchymal clones from human carcinoma cell lines and showed that the epithelial clones were able to generate mesenchymal variants, which had the potential to further produce epithelial revertants autonomously. The successive acquisition of invasive mesenchymal and then epithelial phenotypes recapitulated the steps in tumor progression to metastasis. Importantly, the generation of mesenchymal variants from clonal epithelial populations was associated with subtle changes in chromosome content, which altered the chromosome transcriptome and influenced the expression of genes encoding intercellular junction (IJ) proteins, whereas the loss of chromosome 10p, which harbors the ZEB1 gene, was frequently detected in epithelial variants generated from mesenchymal clones. Knocking down these IJ genes in epithelial cells induced a mesenchymal phenotype, whereas knocking down the ZEB1 gene in mesenchymal cells induced an epithelial phenotype, demonstrating a causal role of chromosome content changes in phenotypic determination. Thus, our studies suggest a paradigm of tumor metastasis: primary epithelial carcinoma cells that lose chromosomes harboring IJ genes acquire an invasive mesenchymal phenotype, and subsequent chromosome content changes such as loss of 10p in disseminated mesenchymal cells generate epithelial variants, which can be selected for to generate epithelial tumors during metastatic colonization.