Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2202-E2209. doi: 10.1073/pnas.1717439115. Epub 2018 Feb 20.
The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E). We and others have shown that eIF4E availability and phosphorylation promote metastasis in mouse models of breast cancer by selectively augmenting the translation of mRNAs involved in invasion and metastasis. However, the impact of translational control in cell types within the tumor microenvironment (TME) is unknown. Here, we demonstrate that regulatory events affecting translation in cells of the TME impact cancer progression. Mice bearing a mutation in the phosphorylation site of eIF4E (S209A) in cells comprising the TME are resistant to the formation of lung metastases in a syngeneic mammary tumor model. This is associated with reduced survival of prometastatic neutrophils due to decreased expression of the antiapoptotic proteins BCL2 and MCL1. Furthermore, we demonstrate that pharmacological inhibition of eIF4E phosphorylation prevents metastatic progression in vivo, supporting the development of phosphorylation inhibitors for clinical use.
mRNA 翻译成蛋白质是基因表达的一个关键调控事件。在癌症中，翻译失调是转化的一个标志，促进了癌细胞的增殖、存活和转移能力。在癌症翻译调控中研究最多的因素是真核翻译起始因子 4E（eIF4E）。我们和其他人已经表明，通过选择性地增强参与侵袭和转移的 mRNA 的翻译，eIF4E 的可用性和磷酸化促进了乳腺癌小鼠模型中的转移。然而，肿瘤微环境（TME）中细胞类型的翻译控制的影响尚不清楚。在这里，我们证明了影响 TME 中细胞翻译的调节事件会影响癌症的进展。在一个同种异体乳腺肿瘤模型中，TME 中细胞的 eIF4E（S209A）磷酸化位点发生突变的小鼠对肺转移的形成具有抗性。这与促转移中性粒细胞的存活减少有关，因为抗凋亡蛋白 BCL2 和 MCL1 的表达减少。此外，我们证明了 eIF4E 磷酸化的药理学抑制可防止体内转移进展，支持开发用于临床的磷酸化抑制剂。
