An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency.
An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency.
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DOI：
10.1016/j.ccell.2016.03.003
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发表时间：
2016-05-09
期刊：
影响因子：
50.3
通讯作者：
Winslow MM
中科院分区：
文献类型：
--
作者：
Brady JJ;Chuang CH;Greenside PG;Rogers ZN;Murray CW;Caswell DR;Hartmann U;Connolly AJ;Sweet-Cordero EA;Kundaje A;Winslow MM
癌细胞建立致死性转移性病变的能力需要单个癌细胞在远处部位的存活和扩增。控制单个癌细胞克隆生长能力的因素仍然知之甚少。在这里，我们发现转录因子ARNTL2的高表达预示着肺腺癌患者预后不良。Arntl2是体内转移能力和细胞培养物中克隆生长所必需的。Arntl2通过协调复杂的促转移分泌蛋白质组的表达来驱动转移性自给自足。我们确定时钟作为Arntl2的合作伙伴和功能验证的基质细胞蛋白Smoc 2作为促转移分泌因子。这些发现揭示了使单个癌细胞在外来组织环境中形成异体肿瘤的分子机制。
The ability of cancer cells to establish lethal metastatic lesions requires the survival and expansion of single cancer cells at distant sites. The factors controlling the clonal growth ability of individual cancer cells remain poorly understood. Here we show that high expression of the transcription factor ARNTL2 predicts poor lung adenocarcinoma patient outcome. Arntl2 is required for metastatic ability in vivo and clonal growth in cell culture. Arntl2 drives metastatic self-sufficiency by orchestrating the expression of a complex pro-metastatic secretome. We identify Clock as an Arntl2 partner and functionally validate the matricellular protein Smoc2 as a pro-metastatic secreted factor. These findings shed light on the molecular mechanisms that enable single cancer cells to form allochthonous tumors in foreign tissue environments.