Fischer et al. reply.
Fischer et al. reply.
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DOI：
10.1038/nature22817
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发表时间：
2017-07-05
期刊：
影响因子：
64.8
通讯作者：
Gao D
中科院分区：
文献类型：
--
作者：
Fischer KR;Altorki NK;Mittal V;Gao D
细胞生物学程序称为上皮细胞间质转化（EMT）已被调用作为Meta过程的一个关键组成部分。相反，Fischer等1最近报道，在两种乳腺肿瘤发育的基因工程小鼠模型中，癌细胞可以在不激活EMT程序的情况下转移。然而，如下文所述，我们发现他们的证据表明EMT程序在这些原发性肿瘤中没有表达是不够的。因此，在他们的分析中不能排除EMT对癌Meta的贡献。Fischer，KR et al. Nature 547，http：//dx. doi。org/10.1038/nature22817（2017）.它已被公认为EMT不是一个单一的，刻板的程序2-4。相反，它代表了一组相关的细胞生物学程序，每个程序都赋予上皮细胞某些间充质性状。它的可变性源于以下事实：（1）它可以通过多种替代性转录因子的表达诱导5-9;（2）激活EMT程序的细胞通常仅部分地朝向完全间充质状态进行，仅获得各种间充质标志物的一部分2、10、11，并且EMT的这种部分和可逆激活已显示对于转移是关键的12-15;以及（3）EMT程序可以在不同组织中以不同方式表现2-4，12。这些考虑有助于阐明Fischer等人1在出版物中分析的EMT程序，他们得出结论，原发性肿瘤的转移发生在EMT激活不存在的情况下。Fischer等人1采用Cre/CreER谱系追踪方法追踪已经经历EMT激活的癌细胞。在这样的遗传追踪方案中，感兴趣的启动子驱动Cre重组酶的表达，这进而在细胞及其直系后代的基因组上施加稳定的遗传标记。这种基本方案的衍生涉及CreER蛋白，其仅在雌激素受体（ER）的配体（在这种情况下为他莫昔芬）存在时起作用。因此，细胞的标记取决于CreER表达和实验补充的他莫昔芬的伴随存在。在目前的情况下，作者使用了Cre可激活的GFP转基因;因此，Cre/CreER的瞬时作用将永久关闭RFP标记并激活GFP报告基因。因此，通过监测GFP的表达，Fischer等1将能够确定这些细胞的祖先是否表达了Cre/CreER。为了使谱系追踪系统有效地标记经历了EMT激活的癌细胞，在我们看来，它需要满足至少两个标准（图1a）。首先，Cre/CreER驱动程序需要在大多数（如果不是全部）瞬时经历EMT激活的细胞中表达。第二，一旦表达，Cre/CreER蛋白需要在大多数（如果不是全部）表达Cre/CreER的癌细胞中激活GFP报告基因。
The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) has been invoked as a critical component of the meta static process. Contrastingly, Fischer et al. 1 recently reported that in two genetically engineered mouse models of mammary tumour deve lopment, carcinoma cells could metastasize without activating EMT programs. However, as detailed below, we find their evidence that EMT programs were not expressed in these primary tumours to be insufficient. Therefore, the contribution of EMT to carcinoma meta stasis could not be ruled out in their analysis. There is a Reply to this Comment by Fischer, KR et al. Nature 547, http://dx. doi. org/10.1038/nature22817 (2017). It has been well-established that the EMT is not a single, stereotypical program 2–4. Instead, it represents a group of related cell-biological programs, each of which confers certain mesenchymal traits on epithelial cells. Its variability stems from the facts that (1) it can be induced by expression of multiple alternative transcription factors 5–9;(2) cells activating an EMT program often proceed only part-way towards a fully mesenchymal state, acquiring only a fraction of various mesenchymal markers 2, 10, 11 and such partial and reversible activation of EMT has been shown to be critical for metastasis 12–15; and (3) EMT programs may be manifested in different ways in different tissues 2–4, 12. These considerations help to illuminate the EMT programs analysed in the publications by Fischer et al. 1, who concluded that metastasis from primary tumours occurred in the absence of EMT activation. Fischer et al. 1 employed the Cre/CreER lineage-tracing method to track carcinoma cells that have undergone EMT activation. In such a genetic tracing protocol, the promoter of interest drives the expression of the Cre recombinase, which in turn inflicts a stable genetic mark on the genome of a cell and its lineal descendants. A derivation of this basic protocol involves a CreER protein, which only functions when a ligand of the oestrogen receptor (ER), in this case tamoxifen, is present. Hence, the marking of a cell depends on the concomitant presence of CreER expression and experimentally supplemented tamoxifen. In the present case, the authors used a Cre-activatable GFP transgene; accordingly, transient actions of Cre/CreER would permanently turn off an RFP marker and activate a GFP reporter. By monitoring the expression of GFP, Fischer et al. 1 would therefore be able to determine whether an ancestor of these cells had expressed Cre/CreER.In order for the lineage tracing system to effectively mark carcinoma cells that have undergone EMT activation, it needs to meet, in our view, at least two criteria (Fig. 1a). First, the Cre/CreER driver needs to be expressed in most if not all of the cells that transiently undergo EMT activation. Second, once expressed, the Cre/CreER protein needs to activate the GFP reporter in most if not all of the carcinoma cells where Cre/CreER is expressed.
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影响因子：
64.5
作者：
Cheung KJ;Gabrielson E;Werb Z;Ewald AJ
通讯作者：
Ewald AJ
影响因子：
64.8
作者：
Fischer KR;Durrans A;Lee S;Sheng J;Li F;Wong ST;Choi H;El Rayes T;Ryu S;Troeger J;Schwabe RF;Vahdat LT;Altorki NK;Mittal V;Gao D
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影响因子：
11.2
作者：
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通讯作者：
Tran DD
DOI：
10.1073/pnas.1508541113
发表时间：
2016-02-16
影响因子：
11.1
作者：
Cheung, Kevin J.;Padmanaban, Veena;Ewald, Andrew J.
通讯作者：
Ewald, Andrew J.
上皮到间质转变对于转移是可分配的，但诱导胰腺癌的化学抗性。
影响因子：
64.8
作者：
Zheng X;Carstens JL;Kim J;Scheible M;Kaye J;Sugimoto H;Wu CC;LeBleu VS;Kalluri R
通讯作者：
Kalluri R