Abstract 3946: Chromosome instability drives phenotypic switching to metastasis

Abstract 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 is required for metastasis. We isolated epithelial (E) and mesenchymal (M) clones from human carcinoma cell lines and showed that the E 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, while the loss of chromosome 10p, which harbors the ZEB1 gene, was frequently detected in epithelial variants generated from M clones. Knocking down these IJ genes in E cells induced a mesenchymal phenotype, while knocking down the ZEB1 gene in M cells induced an epithelial phenotype, demonstrating a causal role of chromosome content changes in phenotypic determination. Thus, our studies suggest a novel 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. Citation Format: Chong-Feng Gao, Yanli Su, Julie Koeman, Curt Essenberg, Karl Dykema, Eric Hudson, Sok Kean Khoo, George Vande Woude. Chromosome instability drives phenotypic switching to metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3946. doi:10.1158/1538-7445.AM2017-3946