Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis
Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis
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DOI：
10.1002/embj.201386082
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发表时间：
2014-03-03
期刊：
影响因子：
11.4
通讯作者：
Kim, Carla F.
中科院分区：
文献类型：
--
作者：
Lau, Allison N.;Curtis, Stephen J.;Kim, Carla F.
转移是肺癌患者发病的主要原因。本研究表明，在原位移植实验中，具有Sca1和CD24标记的小鼠肿瘤增殖细胞（TPCs）具有丰富的转移潜力。CD24敲除降低了类似TPCs的肺癌细胞系的转移潜能。在肺癌患者数据集中，转移性扩散和患者生存可以用小鼠肺TPC基因标记进行分层。在Hippo信号通路中，TPC信号被富集。Hippo介质Yap1或Taz的敲低降低了转移性疾病的体外细胞迁移和移植。此外，本构活性Yap足以在体内驱动肺肿瘤的进展。这些结果证明了两种不同的途径，cd24依赖途径和Yap/ taz依赖途径在肺肿瘤的传播和转移中的功能作用。这项研究证明了TPCs在识别导致转移性肺癌的分子方面的效用，有可能使这种毁灭性疾病的治疗靶向成为可能。
Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease.