Metabolic reprogramming of non‐cancer cells residing in a tumor microenvironment, as a result of the adaptations to cancer‐derived metabolic and non‐metabolic factors, is an emerging aspect of cancer–host interaction. We show that in normal and cancer‐associated fibroblasts, breast cancer‐secreted extracellular vesicles suppress mTOR signaling upon amino acid stimulation to globally reduce mRNA translation. This is through delivery of cancer‐derived miR‐105 and miR‐204, which target RAGC, a component of Rag GTPases that regulate mTORC1 signaling. Following amino acid starvation and subsequent re‐feeding, ¹³C‐arginine labeling of de novo synthesized proteins shows selective translation of proteins that cluster to specific cellular functional pathways. The repertoire of these newly synthesized proteins is altered in fibroblasts treated with cancer‐derived extracellular vesicles, in addition to the overall suppressed protein synthesis. In human breast tumors, RAGC protein levels are inversely correlated with miR‐105 in the stroma. Our results suggest that through educating fibroblasts to reduce and re‐prioritize mRNA translation, cancer cells rewire the metabolic fluxes of amino acid pool and dynamically regulate stroma‐produced proteins during periodic nutrient fluctuations.

中文翻译：

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癌症分泌的 miRNA 调节氨基酸诱导的 mTORC1 信号传导和成纤维细胞蛋白合成


由于对癌症衍生的代谢和非代谢因素的适应，驻留在肿瘤微环境中的非癌细胞的代谢重编程是癌症与宿主相互作用的一个新兴方面。我们发现，在正常和癌症相关的成纤维细胞中，乳腺癌分泌的细胞外囊泡在氨基酸刺激后抑制 mTOR 信号传导，从而整体减少 mRNA 翻译。这是通过传递癌症来源的 miR-105 和 miR-204 来实现的，它们靶向 RAGC，RAGC 是调节 mTORC1 信号传导的 Rag GTPases 的一个组成部分。氨基酸饥饿和随后的重新喂养后，从头合成的蛋白质的¹³ C-精氨酸标记显示蛋白质的选择性翻译，聚集到特定的细胞功能途径。在用癌症来源的细胞外囊泡处理的成纤维细胞中，除了总体抑制的蛋白质合成之外，这些新合成的蛋白质的全部成分也发生了改变。在人类乳腺肿瘤中，RAGC 蛋白水平与基质中的 miR-105 呈负相关。我们的结果表明，通过教育成纤维细胞减少和重新优先考虑 mRNA 翻译，癌细胞重新连接氨基酸库的代谢通量，并在周期性营养波动期间动态调节基质产生的蛋白质。