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

Abstract

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.

Translational repression of Ccl5 and Cxcl10 by 4E‐BP1 and 4E‐BP2 restrains the ability of mouse macrophages to induce migration of activated T cells

“…Of note, polysome-profiling of WT and eIF4E S209A KI MEFs quantified by microarray did not identify Ccl5 and Cxcl10 as targets of translational control via the MNK1/2-eIF4E axis [33]. Moreover, a later study from the same group did not report any differences in CCL5 and CXCL10 serum levels between tumorbearing WT and eIF4E S209A KI mice [44]. In line with these data, we observed that LPS-stimulated WT and eIF4E S209A KI BMDM secrete similar levels of CCL5 and CXCL10.…”

“…*p < 0.05; **p < 0.01; ***p < 0.001. transcripts relies on the MNK1/2-eIF4E axis [11,22,23,33,34,43]. In regards to CCL5 and CXCL10, several lines of evidence indicate that MNK1/2 regulate their expression through different mechanisms [14,33,34,44]. Activation of MNK1/2 was shown to be required for late transcription of Ccl5 mRNA via translational control of the transcription factor RFLAT-1 in IL-2-treated T cells [34].…”

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

“…The study also established that a selective inhibitor of Mnk1/2 strongly blocks migration of fibroblasts and cancer cells besides reducing the expression of vimentin, a marker of mesenchymal cells. In addition, Sonenberg and colleagues provided a rationale for targeting eIF4E phosphorylation in both cancer cells and cells that comprise the TME to halt metastasis and demonstrated the efficacy of this strategy using merestinib, and Mnk1/2 inhibitor (Robichaud et al, 2018). In this study, we provide compelling evidence from both cell lines and animal studies that, in addition to its effects on the primary tumor, VNLG-152R also has anti-metastatic effects.…”

“…Two recent studies demonstrated that pharmacologic inhibition of eIF4E with ribavirin (Pettersson et al, 2015) or inhibition of eIF4E phosphorylation with a multikinase inhibitor that is a potent Mnk1/2 inhibitor, merestinib (Robichaud et al, 2018) potently prevented metastasis of highly aggressive mammary cancer 66c14 cells but exhibited modest/no effect on primary tumor growth. The fact that our studies demonstrate potent inhibition of both primary mammary tumor growth and metastasis, would suggest that Mnk1/2 degraders are more likely to achieve more favorable clinical responses than Mnk1/2 inhibitors in breast cancer patients.…”

The interplay between neutrophils and microbiota in cancer

“…Some groups believe that neutrophils do not undergo a transcriptional switch so much as a change in "state of activation," 181 however numerous studies have shown that neutrophils are still transcriptionally active and proliferative after they leave the bone marrow, 38,178,182,183 including immature Ly6G lo , CXCR2 − , CD101 − murine neutrophils found in tumors. 38 Furthermore, as neutrophils receive multiple prosurvival (IL-8, BCL2, MCL1) 148,184 and granulopoietic (G-CSF, CXCL1, IL-8) 78,96-98 signals from tumors, the early stage cytotoxic N1 TAN could possibly survive long enough within the tumor microenvironment to differentiate in situ into a tumor-promoting late stage N2 TAN. 47,185 This programing switch may occur systemically, not just in the tumor.…”