Chromosome instability drives phenotypic switching to metastasis.

Chromosome instability(CIN) is the most striking feature of human cancers. However, how CIN drives tumor progressionto metastasis remains elusive. Here we studied the role of chromosome content changes in generating the phenotypicdynamics that are required for metastasis. We isolated epithelial and mesenchymalclones from human carcinoma cell lines and showed that the epithelial clones were able to generate mesenchymalvariants, which had the potential to further produce epithelial revertants autonomously. The successive acquisition of invasive mesenchymaland then epithelial phenotypesrecapitulated the steps in tumor progressionto metastasis. Importantly, the generation of mesenchymalvariants 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 mesenchymalclones. Knocking down these IJ genes in epithelial cells induced a mesenchymal phenotype, whereas knocking down the ZEB1 gene in mesenchymalcells induced an epithelial phenotype, demonstrating a causal role of chromosome content changes in phenotypicdetermination. 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 mesenchymalcells generate epithelial variants, which can be selected for to generate epithelial tumors during metastatic colonization.