Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis
Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis
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DOI：
10.1126/science.aay0939
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发表时间：
2020-03-27
期刊：
影响因子：
56.9
通讯作者：
Micalizzi, Douglas S.
中科院分区：
文献类型：
--
作者：
Ebright, Richard Y.;Lee, Sooncheol;Micalizzi, Douglas S.
循环肿瘤细胞(CTC)从原发肿瘤进入血流，但这些细胞中只有一小部分会发生转移。我们在乳腺癌患者的CTC中进行了体内全基因组CRISPR激活筛选，以确定促进小鼠远处转移的基因。编码核糖体蛋白和翻译调节因子的基因在这个筛选中得到了丰富。RPL15编码大的核糖体亚基的一个组成部分，它的过表达增加了多个器官的转移生长，并选择性地增强了其他核糖体蛋白和细胞周期调节因子的翻译。对乳腺癌患者新鲜分离的CTCs进行RNA测序，发现一个亚群具有很强的核糖体和蛋白质合成特征；这些CTC表达增殖和上皮标记，并与不良的临床结果相关。针对这一侵袭性CTCs亚群的治疗可能值得探索，作为转移进展的潜在抑制因素。
Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset of these cells generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in CTCs from breast cancer patients to identify genes that promote distant metastasis in mice. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15, which encodes a component of the large ribosomal subunit, increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA sequencing of freshly isolated CTCs from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these CTCs expressed proliferation and epithelial markers and correlated with poor clinical outcome. Therapies targeting this aggressive subset of CTCs may merit exploration as potential suppressors of metastatic progression.