1. Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal Transition
- Author
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Wilhelm Haas, Ken Tajima, Nicola Aceto, Min Yu, Rémi Buisson, Myriam Boukhali, Valentine Comaills, Daniel A. Haber, Joseph A. LiCausi, Srinjoy Sil, Lee Zou, Tilak K. Sundaresan, Lilian Kabeche, David T. Miyamoto, Nicole Vincent Jordan, Marissa W. Madden, Toshifumi Yae, Shiwei Pan, Shyamala Maheswaran, Robert Morris, Sridhar Ramaswamy, Yu Zheng, and David T. Ting
- Subjects
0301 basic medicine ,Genome instability ,Stromal cell ,Epithelial-Mesenchymal Transition ,Medical Physiology ,Breast Neoplasms ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Genomic Instability ,Cell Line ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Circulating tumor cell ,Stem Cell Research - Nonembryonic - Human ,Cell Line, Tumor ,Breast Cancer ,medicine ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Epithelial–mesenchymal transition ,Aetiology ,Mitosis ,Cell Proliferation ,Cancer ,Tumor ,Lamin Type B ,Mesenchymal stem cell ,Human Genome ,Cell Differentiation ,medicine.disease ,Stem Cell Research ,Cell biology ,030104 developmental biology ,Cancer cell ,Female ,Biochemistry and Cell Biology ,Biotechnology - 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.
- Published
- 2016