研究揭示促進(jìn)乳腺癌轉(zhuǎn)移的新動(dòng)力
2020-02-12
來(lái)源：小柯機(jī)器人
美國(guó)哈佛醫(yī)學(xué)院Shyamala Maheswaran和Daniel A. Haber合作，發(fā)現(xiàn)核糖體蛋白表達(dá)和翻譯的失調(diào)會(huì)促進(jìn)乳腺癌轉(zhuǎn)移。該研究2020年2月6日在線發(fā)表于國(guó)際學(xué)術(shù)期刊《科學(xué)》。
研究人員對(duì)源自乳腺癌患者的循環(huán)腫瘤細(xì)胞（CTC）進(jìn)行了體內(nèi)全基因組CRISPR激活篩選，以鑒定在小鼠中促進(jìn)遠(yuǎn)處轉(zhuǎn)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(gè)組分，其過表達(dá)促進(jìn)癌癥細(xì)胞在多個(gè)器官的轉(zhuǎn)移性生長(zhǎng)，并選擇性增強(qiáng)了其他核糖體蛋白和細(xì)胞周期調(diào)節(jié)因子的翻譯。對(duì)來(lái)自乳腺癌患者新分離出的CTCs 進(jìn)行RNA測(cè)序,研究人員發(fā)現(xiàn)一個(gè)具有強(qiáng)核糖體和蛋白質(zhì)合成特征的亞組。這些CTCs表達(dá)增殖和上皮細(xì)胞的標(biāo)志物，并與臨床的不良預(yù)后相關(guān)。 針對(duì)這群惡化的CTC細(xì)胞的治療可作為轉(zhuǎn)移進(jìn)程潛在抑制劑進(jìn)行研究。
據(jù)了解，CTCs從原發(fā)腫瘤脫落進(jìn)入血液，但只有一小部分會(huì)發(fā)生轉(zhuǎn)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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