Abstract 1410: Proliferation during epithelial-to-mesenchymal transition induces genomic instability

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Abstract Epithelial to mesenchymal transition (EMT), a morphogenetic process required for proper embryonic development, is adopted by cancer cells during tumor progression. We show that induction of EMT by TGFß or other EMT-inducers such as Snail leads to genomic instability, associated with failed cytokinesis and chromosome missegregation resulting in aneuploidy and polyploidy. These defects are dependent on persistent proliferation of cells undergoing EMT and are absent in normal cells that growth arrest during EMT. While EMT and the associated mitotic abnormalities are reversible upon removal of the EMT-inducer, the resulting chromosomal abnormalities are inherited. TGFß-induced genomic instability is associated with the acquisition of tumorigenic phenotypes and the resulting tumors are enriched for a genomically-altered tumor cell population, which exhibits differential drug sensitivity. In breast and prostate cancer cells circulating in the blood, TGFß and EMT gene signatures are significantly correlated with aneuploid gene signatures. Analysis of single circulating tumor cells (CTC) from women with metastatic breast cancer reveals increased in genomic instability in mesenchymal CTCs. Together, these findings identify a novel mechanism whereby tumor microenvironment-derived signals impact heritable genetic changes within cancer cells. Citation Format: Valentine Comaills, Lilian Kabeche, Robert Morris, Min Yu, Marissa Wells Madden, Joseph A. LiCausi, Nicola Aceto, Yu Zheng, David T. Miyamoto, Sridhar Ramaswamy, Lee Zou, Daniel A. Haber, Shyamala Maheswaran. Proliferation during epithelial-to-mesenchymal transition induces genomic instability [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 1410. doi:10.1158/1538-7445.AM2017-1410