title: 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 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.
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503; george.vandewoude@vai.org chongfeng.gao@vai.org.
authors.forename: ChongFeng
authors.initials: C
authors.lastname: Gao
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Su
authors.affiliation: Core Technologies and Services, Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Julie
authors.initials: J
authors.lastname: Koeman
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Haak
authors.affiliation: Core Technologies and Services, Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Karl
authors.initials: K
authors.lastname: Dykema
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Curt
authors.initials: C
authors.lastname: Essenberg
authors.affiliation: Core Technologies and Services, Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Eric
authors.initials: E
authors.lastname: Hudson
authors.affiliation: Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: David
authors.initials: D
authors.lastname: Petillo
authors.affiliation: Department of Cell and Molecular Biology, Grand Valley State University, Grand Rapids, MI 49503.
authors.forename: Sok Kean
authors.initials: SK
authors.lastname: Khoo
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503; george.vandewoude@vai.org chongfeng.gao@vai.org.
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
mesh_terms: D000782:Aneuploidy; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D003001:Cloning, Molecular; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008648:Mesoderm / Q000473:pathology; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D010641:Phenotype
chemical_list: D014408:Biomarkers, Tumor
keywords: aneuploidy; chromosome instability; clonal evolution; epithelial–mesenchymal transition (E-MT); tumor metastasis