The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis.
The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis.
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DOI：
10.1016/j.cub.2016.01.045
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发表时间：
2016-03-21
期刊：
影响因子：
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通讯作者：
Norman JC
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文献类型：
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作者：
Clarke CJ;Berg TJ;Birch J;Ennis D;Mitchell L;Cloix C;Campbell A;Sumpton D;Nixon C;Campbell K;Bridgeman VL;Vermeulen PB;Foo S;Kostaras E;Jones JL;Haywood L;Pulleine E;Yin H;Strathdee D;Sansom O;Blyth K;McNeish I;Zanivan S;Reynolds AR;Norman JC
引发剂蛋氨酸tRNA （tRNAiMet）的表达在癌症中被解除调控。尽管如此，目前尚不清楚tRNAiMet表达水平如何影响肿瘤进展。我们发现tRNAiMet在癌相关成纤维细胞中的表达增加，暗示肿瘤基质中tRNAiMet的表达失调可能是肿瘤进展的一个因素。为了研究间质tRNAiMet升高如何促进肿瘤进展，我们培育了一只表达tRNAiMet基因额外拷贝的小鼠（2+tRNAiMet小鼠）。与野生型对照相比，2+tRNAiMet小鼠皮下肿瘤移植物的生长和血管化增强。2+tRNAiMet小鼠成纤维细胞沉积的细胞外基质支持内皮细胞和成纤维细胞的增强迁移。SILAC质谱分析表明，tRNAiMet的表达升高显著增加了某些类型胶原的合成和分泌，特别是II型胶原。II型胶原的抑制抑制了trnaimet过表达成纤维细胞沉积促迁移ECM的能力。我们使用脯氨酸羟化酶抑制剂乙基-3,4-二羟基苯甲酸酯（DHB）来确定胶原合成是否有助于体内trnaimet驱动的致瘤前基质。DHB对野生型小鼠同种异体移植物的生长没有影响，但与2+tRNAiMet小鼠支持血管生成和肿瘤生长的能力相反。最后，II型胶原表达预示着高级别浆液性卵巢癌的不良预后。综上所述，这些数据表明，tRNAiMet水平的增加通过增强基质成纤维细胞合成和分泌支持内皮细胞迁移和血管生成的富含II型胶原的ECM的能力，促进肿瘤进展。tRNA库与癌症进展之间的机制联系启动器蛋氨酸tRNA水平对分泌组的选择性控制tRNAome与间质成纤维细胞分泌ECM之间的联系一个新的转基因模型概述了癌症tRNAome的一个关键方面Clarke等人表明，在癌相关成纤维细胞中，启动器tRNAiMet的水平升高。他们使用转基因方法概括了这一点，并使用定量质谱法来表征基质分泌组，结果表明，tRNAiMet的升高会促进富含II型胶原蛋白的ECM的产生，从而推动肿瘤的进展。
Expression of the initiator methionine tRNA (tRNAiMet) is deregulated in cancer. Despite this fact, it is not currently known how tRNAiMet expression levels influence tumor progression. We have found that tRNAiMet expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAiMet in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAiMet contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAiMet gene (2+tRNAiMet mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAiMet mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAiMet mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAiMet significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAiMet-overexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAiMet-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNAiMet mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAiMet levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis. A mechanistic link between the tRNA repertoire and cancer progression Selective control of the secretome by levels of the initiator methionine tRNA A link between the tRNAome and ECM secretion from stromal fibroblasts A new transgenic model recapitulating a key aspect of the cancer tRNAome Clarke et al. show that levels of the initiator tRNAiMet are increased in carcinoma-associated fibroblasts. Using a transgenic approach to recapitulate this in vivo and quantitative mass spectrometry to characterize the stromal secretome, they show that elevated tRNAiMet drives production of a type II collagen-rich ECM to drive tumor progression.