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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 10; pp. E2202 - E2209
• Main Authors: Robichaud, Nathaniel, Hsu, Brian E., Istomine, Roman, Alvarez, Fernando, Blagih, Julianna, Ma, Eric H., Morales, Sebastian V., Dai, David L., Li, Glenn, Souleimanova, Margarita, Guo, Qianyu, del Rincon, Sonia V., Miller, Wilson H., Cajal, Santiago Ramón y, Park, Morag, Jones, Russell G., Piccirillo, Ciriaco A., Siegel, Peter M., Sonenberg, Nahum
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06.03.2018
• Series: PNAS Plus
• Subjects: Amino Acid Motifs; Animal models; Animals; Biological Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Cell proliferation; Deregulation; Eukaryotic Initiation Factor-4E - chemistry; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - metabolism; Female; Gene expression; Genetic transformation; Humans; Initiation factor eIF-4E; Leukocytes (neutrophilic); Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lungs; Mammary gland; Mcl-1 protein; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Neoplasm Metastasis; Neutrophils; Neutrophils - metabolism; Pharmacology; Phosphorylation; PNAS Plus; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Survival; Tumor Microenvironment; Tumors; eIF4E; MNK; tumor microenvironment; metastasis; neutrophil
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1717439115

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.