EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells.
EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells.
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DOI：
10.1038/ncomms15773
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发表时间：
2017-06-12
影响因子：
16.6
通讯作者：
Ford HL
中科院分区：
文献类型：
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作者：
Neelakantan D;Zhou H;Oliphant MUJ;Zhang X;Simon LM;Henke DM;Shaw CA;Wu MF;Hilsenbeck SG;White LD;Lewis MT;Ford HL
最近的命运映射研究得出结论，EMT是不需要癌的转移。在这里，我们挑战这一结论，表明这些研究未能解释EMT和非EMT细胞之间可能的串扰，促进非EMT细胞的传播。在乳腺癌模型中，EMT细胞以旁分泌方式诱导弱转移性非EMT肿瘤细胞的转移增加，部分是通过GLI转录因子的非细胞自主激活。GANT 61（一种GLI 1/2抑制剂）治疗，而不是IPI 926（一种Smoothened抑制剂）治疗，阻断了这种作用并抑制了PDX模型的生长。在人类乳腺肿瘤中，EMT转录因子与激活的Hedgehog/GLI信号传导密切相关，但与Hh配体无关。我们的研究结果表明，EMT有助于通过非细胞自主效应，激活Hh通路的转移。尽管所有Hh抑制剂都可以对具有典型Hh/GLI信号传导的肿瘤起作用，但只有GLI抑制剂会对非典型EMT诱导的GLI活化起作用。最近的研究结果已经挑战了上皮细胞间质转化（EMT）在促进肿瘤进展中的中心地位。在这里，作者表明，EMT细胞可以通过非细胞自主激活邻近上皮肿瘤细胞中的GLI转录程序来促进乳腺癌转移。
Recent fate-mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that these studies failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumour cells in a paracrine manner, in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI 926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX models. In human breast tumours, the EMT-transcription factors strongly correlate with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis via non-cell autonomous effects that activate the Hh pathway. Although all Hh inhibitors may act against tumours with canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical EMT-induced GLI activation. Recent findings have challenged the centrality of epithelial-to-mesenchymal transition (EMT) in promoting tumour progression. Here the authors show that EMT cells can promote breast cancer metastasis by non-cell autonomous activation of the GLI transcriptional program in neighbouring epithelial tumour cells.