Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils

Significance Our findings document mRNA translation in cells of the tumor microenvironment (TME) as a crucial factor in metastatic progression. The results underscore the importance of understanding how translation-targeting therapies affect different cell types within the TME. We provide a rationale for targeting eIF4E phosphorylation in both cancer cells and cells that comprise the TME to halt metastasis and demonstrate the efficacy of this strategy using merestinib, a small molecule targeting the mitogen-activated protein kinase integrating kinases (MNKs). Our findings raise the possibility that a combination of MNK inhibitors with immunotherapy represents a therapeutic opportunity worthy of further investigation for treating cancer metastasis. 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.