Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer.
Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer.
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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。
DOI：
10.1038/nature16064
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发表时间：
2015-11-26
期刊：
影响因子：
64.8
通讯作者：
Kalluri R
中科院分区：
文献类型：
--
作者：
Zheng X;Carstens JL;Kim J;Scheible M;Kaye J;Sugimoto H;Wu CC;LeBleu VS;Kalluri R
尽管目前有最好的治疗方法，但胰腺导管腺癌 (PDAC) 的诊断与不良预后相关。因此迫切需要新的治疗策略。大量研究表明上皮间质转化（EMT）有助于癌细胞的早期扩散，并且对于 PDAC 的侵袭和转移至关重要。 EMT与细胞培养条件下上皮细胞向间质样细胞的表型转化有关，尽管体内上皮细胞的这种明确的间质转化（具有纺锤形形态）很少见，在肿瘤中偶尔观察到准间质表型（部分EMT）。大多数探索 EMT 在肿瘤中的功能作用的研究都依赖于细胞培养诱导的功能丧失和功能获得实验，涉及 EMT 诱导转录因子，如 Twist、Snail 和 Zeb1（参考文献 , , , , , ）。因此，EMT 对侵袭和转移的功能贡献仍不清楚，并且缺乏解决因果关系的基因工程小鼠模型。在这里，我们通过生成删除 Snail 或 Twist（负责 EMT 的两个关键转录因子）的 PDAC 小鼠模型，从功能上探讨 EMT 在 PDAC 中的作用。原发肿瘤中的 EMT 抑制不会改变侵袭性 PDAC 的出现、全身播散或转移。抑制 EMT 会导致癌细胞增殖增加，肿瘤中核苷转运蛋白的表达增强，从而增强对吉西他滨治疗的敏感性并增加小鼠的总体存活率。总的来说，我们的研究表明，Snail 或 Twist 诱导的 EMT 并不是侵袭和转移的速率限制，但强调了将 EMT 抑制与化疗结合起来治疗胰腺癌的重要性。
Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC,,,. EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cellsin vivois rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT),. Most studies exploring the functional role of EMT in tumours have depended on cell-culture-induced loss-of-function and gain-of-function experiments involving EMT-inducing transcription factors such as Twist, Snail and Zeb1 (refs , , , , , ). Therefore, the functional contribution of EMT to invasion and metastasis remains unclear,, and genetically engineered mouse models to address a causal connection are lacking. Here we functionally probe the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT. EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis. Suppression of EMT leads to an increase in cancer cell proliferation with enhanced expression of nucleoside transporters in tumours, contributing to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice. Collectively, our study suggests that Snail- or Twist-induced EMT is not rate-limiting for invasion and metastasis, but highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.