20 research outputs found

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

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    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

    mGriPSCs are pluripotent.

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    <p>Using G4-mESCs as a standard <b>(A-D, I)</b>, mGriPSCs are alkaline phosphatase reactive <b>(E)</b> and express stem cell antigens Oct4 <b>(F)</b>, SSEA1 <b>(G)</b> and Nanog <b>(H, I)</b>. mGriPSCS express additional stem cell markers by RT-PCR <b>(I)</b> and are karyotypically normal <b>(J)</b>. mGriPSC express endogenous copies of the introduced reprogramming genes and retroviral [trans] copies are present to varying degrees <b>(K).</b> mGriPSCs form EBs <b>(L)</b> that differentiate into three germ layers—ectodermal neurofilament <b>(M)</b>, and mesodermal SMA <b>(N)</b>, and endoderm alpha-fetoprotein (<b>O,</b> AFP). Teratomas <b>(P)</b> also show differentiation into three germ layers <b>(Q-S)</b>. Scale bars: <b>A-H</b> 20 μm; <b>L</b> 200 μm; <b>M-O, Q-S</b> 10 μm.</p

    Methylation analysis of GC-derived iPS cells shows stem cell reprogramming with retention of target tissue methylation.

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    <p>The stem cell gene Oct4 in mGriPSC is less methylated than it is in GCs (mGriPSC vs. GC, P<0.001) and is therefore more similar to Oct4 in G4 ESCs <b>(A)</b>. Methylation patterns of ovarian and germ cell genes Foxl2 and Figla are comparable in both mGriPSC and GCs (<b>B</b>, Foxl2, P = 0.84; Figla, P = 0.606).</p

    Genome-wide analysis of mRNA and microRNA confirms efficient pluripotent reprogramming of mGriPSCs and hGriPSCs.

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    <p>mGriPSC-EBs and mESC-EBs have comparable microarray expression profiles <b>(A)</b>. All ESC or EB samples show minimal steroidogenic mRNA compared to adult ovary samples <b>(B).</b> Principal component analysis (PCA) indicates attached and unattached mGriPSC-EBs are more disparate relative to the analogous mESC-EBs <b>(C)</b>. microRNA heatmaps support efficient stem cell reprogramming of mGriPSCs <b>(D)</b>.</p
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