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Cell Rep. 2016 Dec 6;17(10):2632-2647. doi: 10.1016/j.celrep.2016.11.022.

Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal Transition.

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA.
2
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
3
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
4
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
5
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.
6
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
7
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: maheswaran@helix.mgh.harvard.edu.

Abstract

TGF-β secreted by tumor stroma induces epithelial-to-mesenchymal transition (EMT) in cancer cells, a reversible phenotype linked to cancer progression and drug resistance. However, exposure to stromal signals may also lead to heritable changes in cancer cells, which are poorly understood. We show that epithelial cells failing to undergo proliferation arrest during TGF-β-induced EMT sustain mitotic abnormalities due to failed cytokinesis, resulting in aneuploidy. This genomic instability is associated with the suppression of multiple nuclear envelope proteins implicated in mitotic regulation and is phenocopied by modulating the expression of LaminB1. While TGF-β-induced mitotic defects in proliferating cells are reversible upon its withdrawal, the acquired genomic abnormalities persist, leading to increased tumorigenic phenotypes. In metastatic breast cancer patients, increased mesenchymal marker expression within single circulating tumor cells is correlated with genomic instability. These observations identify a mechanism whereby microenvironment-derived signals trigger heritable genetic changes within cancer cells, contributing to tumor evolution.

PMID:
27926867
PMCID:
PMC5320932
DOI:
10.1016/j.celrep.2016.11.022
[Indexed for MEDLINE]
Free PMC Article

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