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

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. [Display omitted] •Two cap-dependent mRNA translation mechanisms promote tumor progression•eIF4E/mTORC1 is required for cancer cell proliferation and survival•DAP5/eIF3d is required for the cancer cell EMT, cell migration, and metastasis•Inhibition of DAP5 strongly reduces metastasis and survival of metastases Alard et al. show that cancer cell mRNA translation involves two distinct cap-dependent mRNA translation mechanisms, one directed by canonical eIF4E/mTORC1 and the other by specialized DAP5/eIF3d. A surprising level of plasticity exists in mRNA translation during cancer progression and metastasis.