Breast cancer cell mesenchymal transition and metastasis directed by DAP5/eIF3d-mediated selective mRNA translation

Cell Rep. 2023 Jun 27;42(6):112646. doi: 10.1016/j.celrep.2023.112646. Epub 2023 Jun 13.

Abstract

Cancer cell plasticity enables cell survival in harsh physiological environments and fate transitions such as the epithelial-to-mesenchymal transition (EMT) that underlies invasion and metastasis. Using genome-wide transcriptomic and translatomic studies, an alternate mechanism of cap-dependent mRNA translation by the DAP5/eIF3d complex is shown to be essential for metastasis, EMT, and tumor directed angiogenesis. DAP5/eIF3d carries out selective translation of mRNAs encoding EMT transcription factors and regulators, cell migration integrins, metalloproteinases, and cell survival and angiogenesis factors. DAP5 is overexpressed in metastatic human breast cancers associated with poor metastasis-free survival. In human and murine breast cancer animal models, DAP5 is not required for primary tumor growth but is essential for EMT, cell migration, invasion, metastasis, angiogenesis, and resistance to anoikis. Thus, cancer cell mRNA translation involves two cap-dependent mRNA translation mechanisms, eIF4E/mTORC1 and DAP5/eIF3d. These findings highlight a surprising level of plasticity in mRNA translation during cancer progression and metastasis.

Keywords: CP: Cancer; CP: Molecular biology; DAP5; breast cancer; epithelial-to-mesenchymal transition; metastasis; protein synthesis; translation initiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms* / genetics
  • Cell Line, Tumor
  • Cell Movement
  • Epithelial-Mesenchymal Transition / genetics
  • Eukaryotic Initiation Factor-3* / genetics
  • Eukaryotic Initiation Factor-3* / metabolism
  • Eukaryotic Initiation Factor-4G* / genetics
  • Eukaryotic Initiation Factor-4G* / metabolism
  • Female
  • Humans
  • Mice
  • Neoplasm Metastasis
  • Protein Biosynthesis*
  • RNA, Messenger / genetics
  • Transcription Factors / genetics

Substances

  • Eukaryotic Initiation Factor-4G
  • RNA, Messenger
  • Transcription Factors
  • EIF3D protein, human
  • Eukaryotic Initiation Factor-3