The pathogenesis of mesothelioma is driven by a dysregulated translatome.
The pathogenesis of mesothelioma is driven by a dysregulated translatome.
复制标题
DOI：
10.1038/s41467-021-25173-7
复制
发表时间：
2021-08-13
影响因子：
16.6
通讯作者：
Willis AE
中科院分区：
文献类型：
--
作者：
Grosso S;Marini A;Gyuraszova K;Voorde JV;Sfakianos A;Garland GD;Tenor AR;Mordue R;Chernova T;Morone N;Sereno M;Smith CP;Officer L;Farahmand P;Rooney C;Sumpton D;Das M;Teodósio A;Ficken C;Martin MG;Spriggs RV;Sun XM;Bushell M;Sansom OJ;Murphy D;MacFarlane M;Le Quesne JPC;Willis AE
恶性间皮瘤（MpM）是一种侵袭性且总是致命的肿瘤，与石棉暴露有因果关联。该疾病主要源于肿瘤抑制基因功能缺失，且不存在与MpM相关的“可成药”驱动癌基因。为了确定这种疾病的治疗机会，我们进行了多聚核糖体图谱分析以确定MpM的翻译组。我们发现，在MpM中，编码核糖体组装和线粒体生物发生所需蛋白质的信使核糖核酸（mRNA）的翻译有选择性增加。这导致mRNA翻译速率提高、线粒体形态和耗氧量异常，以及代谢产物的重新编程。这些改变限制了细胞蛋白质生物合成的能力，加速了生长并推动了疾病进展。重要的是，我们表明抑制mRNA翻译，特别是通过对雷帕霉素靶蛋白复合物1（mTORC1）和2进行联合药物靶向，可逆转这些变化，并在体外以及来自终末期疾病患者的离体肿瘤组织中抑制恶性细胞生长。关键的是，我们表明这些药物干预措施可延长石棉诱导的间皮瘤动物模型的生存期，为这种无法治愈的疾病的患者提供了一种有针对性的、可行的治疗选择基础。
由于缺乏可成药基因，治疗恶性胸膜间皮瘤（MpM）具有挑战性，但其他分子特征可能在临床上有用。在这里，作者使用多聚核糖体图谱分析描绘了MpM细胞系中mRNA翻译失调的情况，并确定mTORC1和2为潜在的药物靶点。
Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no ‘druggable’ driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease. Treating malignant pleural mesothelioma (MpM) is challenging due to a lack of druggable genes, but other molecular features could be clinically useful. Here the authors profile mRNA translation dysregulation in MpM cell lines using polysome profiling, and identify mTORC1 and 2 as potential pharmacological targets.
登录
查看更多内容
影响因子：
28.2
作者：
Hmeljak J;Sanchez-Vega F;Hoadley KA;Shih J;Stewart C;Heiman D;Tarpey P;Danilova L;Drill E;Gibb EA;Bowlby R;Kanchi R;Osmanbeyoglu HU;Sekido Y;Takeshita J;Newton Y;Graim K;Gupta M;Gay CM;Diao L;Gibbs DL;Thorsson V;Iype L;Kantheti H;Severson DT;Ravegnini G;Desmeules P;Jungbluth AA;Travis WD;Dacic S;Chirieac LR;Galateau-Sallé F;Fujimoto J;Husain AN;Silveira HC;Rusch VW;Rintoul RC;Pass H;Kindler H;Zauderer MG;Kwiatkowski DJ;Bueno R;Tsao AS;Creaney J;Lichtenberg T;Leraas K;Bowen J;TCGA Research Network;Felau I;Zenklusen JC;Akbani R;Cherniack AD;Byers LA;Noble MS;Fletcher JA;Robertson AG;Shen R;Aburatani H;Robinson BW;Campbell P;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
14.9
作者：
Haft DH;DiCuccio M;Badretdin A;Brover V;Chetvernin V;O'Neill K;Li W;Chitsaz F;Derbyshire MK;Gonzales NR;Gwadz M;Lu F;Marchler GH;Song JS;Thanki N;Yamashita RA;Zheng C;Thibaud-Nissen F;Geer LY;Marchler-Bauer A;Pruitt KD
通讯作者：
Pruitt KD
影响因子：
8
作者：
Altomare, DA;You, HH;Testa, JR
通讯作者：
Testa, JR
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
5.7
作者：
Guichard, Sylvie M.;Curwen, Jon;Cosulich, Sabina C.
通讯作者：
Cosulich, Sabina C.