Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance.
Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance.
复制标题
DOI：
10.1038/nature15748
复制
发表时间：
2015-11-26
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;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
上皮间质转化（EMT）在转移中的作用是一个长期存在争议的来源，主要是由于无法在体内监测瞬时和可逆的EMT表型。我们建立了一个EMT谱系追踪系统来监测这一过程，在自发性乳腺至肺转移模型中使用间质特异性Cre介导的荧光标记开关系统。我们证实，在一个主要是上皮原发性肿瘤，一小部分肿瘤细胞进行EMT。引人注目的是，肺转移瘤主要由维持其上皮表型的非EMT肿瘤细胞组成。通过过表达miR-200抑制EMT并不影响肺转移的发展。然而，EMT细胞显着有助于化疗后复发性肺转移形成。这些细胞存活环磷酰胺治疗由于减少增殖，凋亡耐受，和耐药相关基因的表达升高。miR-200的过表达消除了这种抗性。这项研究表明，EMT靶向策略与常规化疗相结合，用于乳腺癌治疗的潜力。
The role of epithelial to mesenchymal transition (EMT) in metastasis is a longstanding source of controversy, largely due to an inability to monitor transient and reversible EMT phenotypes in vivo. We established an EMT lineage tracing system to monitor this process, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We confirmed that within a predominantly epithelial primary tumor, a small portion of tumor cells undergo EMT. Strikingly, lung metastases mainly consisted of non-EMT tumor cells maintaining their epithelial phenotype. Inhibiting EMT by overexpressing miR-200 did not impact lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment due to reduced proliferation, apoptotic tolerance, and elevated expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment.