研究揭示促進乳腺癌轉移的新動力
美國哈佛醫(yī)學院Shyamala Maheswaran和Daniel A. Haber合作，發(fā)現(xiàn)核糖體蛋白表達和翻譯的失調(diào)會促進乳腺癌轉移。該研究2020年2月6日在線發(fā)表于國際學術期刊《科學》。
研究人員對源自乳腺癌患者的循環(huán)腫瘤細胞（CTC）進行了體內(nèi)全基因組CRISPR激活篩選，以鑒定在小鼠中促進遠處轉移的基因。在此篩選中，研究人員鑒定了豐富的核糖體蛋白編碼基因和翻譯調(diào)節(jié)因子。RPL15編碼核糖體大亞基的一個組分，其過表達促進癌癥細胞在多個器官的轉移性生長，并選擇性增強了其他核糖體蛋白和細胞周期調(diào)節(jié)因子的翻譯。對來自乳腺癌患者新分離出的CTCs 進行RNA測序,研究人員發(fā)現(xiàn)一個具有強核糖體和蛋白質合成特征的亞組。這些CTCs表達增殖和上皮細胞的標志物，并與臨床的不良預后相關。 針對這群惡化的CTC細胞的治療可作為轉移進程潛在抑制劑進行研究。
據(jù)了解，CTCs從原發(fā)腫瘤脫落進入血液，但只有一小部分會發(fā)生轉移。
附：英文原文
Title: Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis
Author: Richard Y. Ebright, Sooncheol Lee, Ben S. Wittner, Kira L. Niederhoffer, Benjamin T. Nicholson, Aditya Bardia, Samuel Truesdell, Devon F. Wiley, Benjamin Wesley, Selena Li, Andy Mai, Nicola Aceto, Nicole Vincent-Jordan, Annamaria Szabolcs, Brian Chirn, Johannes Kreuzer, Valentine Comaills, Mark Kalinich, Wilhelm Haas, David T. Ting, Mehmet Toner, Shobha Vasudevan, Daniel A. Haber, Shyamala Maheswaran, Douglas S. Micalizzi
Issue&Volume: 2020/02/06
Abstract: AbstractCirculating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in breast cancer patient-derived CTCs to identify genes that promote their 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.
DOI: 10.1126/science.aay0939
Source: https://science.sciencemag.org/content/early/2020/02/05/science.aay0939
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