Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 10, Pages E2202-E2209Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1717439115
Keywords
metastasis; neutrophil; eIF4E; MNK; tumor microenvironment
Categories
Funding
- Susan G. Komen Breast Cancer Foundation [IIR12224057]
- Canadian Institutes of Health Research (CIHR) [FDN-148423]
- Canadian Cancer Society [2010-700377]
- TFRI Team Grant [TFF-116128, TFF-242122]
- Cancer Research Society [2015-20239, 2015-20042]
- CIHR [PJT-148821]
- Reseau de Recherche en Cancer of the Fonds de la Recherche en Sante du Quebec (FRQS) [FRQ-34787]
- Quebec Breast Cancer Foundation
- Vanier Canada Graduate Scholarship [267839]
- Rosalind Goodman Commemorative Scholarship (GCRC)
- McGill Integrated Cancer Research Training Program (GCRC)
- McGill Faculty of Medicine
- Karassik Foundation (GCRC)
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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.
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