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Distinct EMT programs control normal mammary stem cells and tumour-initiating cells

机译：独特的EMT程序控制正常的乳腺干细胞和肿瘤引发细胞

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摘要

Tumour-initiating cells (TICs) are responsible for metastatic dissemination and clinical relapse in a variety of cancers(1,2). Analogies between TICs and normal tissue stem cells have led to the proposal that activation of the normal stem-cell program within a tissue serves as the major mechanism for generating TICs3-7. Supporting this notion, we and others previously established that the Slug epithelial-to-mesenchymal transition-inducing transcription factor (EMT-TF), a member of the Snail family, serves as a master regulator of the gland-reconstituting activity of normal mammary stem cells, and that forced expression of Slug in collaboration with Sox9 in breast cancer cells can efficiently induce entrance into the TIC state(8). However, these earlier studies focused on xenograft models with cultured cell lines and involved ectopic expression of EMT-TFs, often at non-physiological levels. Using genetically engineered knock-in reporter mouse lines, here we show that normal gland-reconstituting mammary stem cells(9-11) residing in the basal layer of the mammary epithelium and breast TICs originating in the luminal layer exploit the paralogous EMT-TFs Slug and Snail, respectively, which induce distinct EMT programs. Broadly, our findings suggest that the seemingly similar stem-cell programs operating in TICs and normal stem cells of the corresponding normal tissue are likely to differ significantly in their details.
机译：肿瘤起始细胞（TICs）负责多种癌症的转移扩散和临床复发（1,2）。 TIC与正常组织干细胞之间的类比导致提出这样的建议，即激活组织内正常干细胞程序是产生TICs3-7的主要机制。支持这一观点，我们和其他人先前建立了Snail家族成员Slug上皮-间充质转化诱导转录因子（EMT-TF），作为正常乳腺腺体重建活动的主要调节剂。 Sug和Sox9在乳腺癌细胞中的强制表达可以有效诱导进入TIC状态（8）。然而，这些较早的研究集中于具有培养的细胞系的异种移植模型，并且涉及EMT-TFs的异位表达，通常处于非生理水平。使用基因工程敲入的报告基因小鼠系，我们显示了位于乳腺上皮基底层的正常腺重组乳腺干细胞（9-11）和源自腔层的乳腺TICs利用了同源的EMT-TFs Slug和Snail分别引发了不同的EMT程序。概括地说，我们的发现表明，在TIC中运行的看似相似的干细胞程序与相应正常组织的正常干细胞在细节上可能存在显着差异。

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  • 来源
    《Nature》 |2015年第7568期|256-260|共5页
  • 作者

    Ye Xin; Tam Wai Leong; Shibue Tsukasa; Kaygusuz Yasemin; Reinhardt Ferenc; Eaton Elinor Ng; Weinberg Robert A.;

  • 作者单位

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA;

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA|Genome Inst Singapore, Singapore 138672, Singapore|Canc Sci Inst Singapore, Singapore 117599, Singapore;

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA;

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA;

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA;

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA;

    Whitehead Inst Biomed Res, Cambridge, MA 02142 USA|MIT, Dept Biol, Cambridge, MA 02139 USA|MIT, Ludwig Ctr Mol Oncol, Cambridge, MA 02139 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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