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Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):14793-14798. doi: 10.1073/pnas.1618215113. Epub 2016 Dec 5.

Chromosome instability drives phenotypic switching to metastasis.

Author information

1
Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503; george.vandewoude@vai.org chongfeng.gao@vai.org.
2
Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503.
3
Core Technologies and Services, Van Andel Research Institute, Grand Rapids, MI 49503.
4
Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI 49503.
5
Department of Cell and Molecular Biology, Grand Valley State University, Grand Rapids, MI 49503.

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.

KEYWORDS:

aneuploidy; chromosome instability; clonal evolution; epithelial–mesenchymal transition (E-MT); tumor metastasis

PMID:
27930335
PMCID:
PMC5187712
DOI:
10.1073/pnas.1618215113
[Indexed for MEDLINE]
Free PMC Article

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