Src promotes tumor cell invasion by hijacking the translation machinery

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Bonnard, Benjamin | Chatefau, Anouk | Dourthe, Cyril | Tommaso, Sylvaine Di | Dupuy, Jean-William | Mahouche, Isabelle | Solorzano, Jacobo | Bras, Morgane Le | Raymond, Anne-Aurélie | Moreau, Violaine | Jabouille, Arnaud | Blangy, Anne | Martineau, Yvan | Saltel, Frédéric

Edité par CCSD ; BioRxiv -

International audience. Abstract The Src oncogene controls cancer cell invasiveness by promoting invadosome formation and extracellular matrix degradation (ECM). Invadosomes are enriched in the eukaryotic translation initiation factor 3 (eIF3) complex associated with a local mRNA translation activity mandatory for their maintenance. Here, we show that Src regulates mRNA translation by controlling the expression of eIF3 subunits. Among them, eIF3h/e/d are essential for invadosome formation and ECM degradation. We demonstrate that Src controls the canonical mTOR/eIF4E and the non-canonical eIF3d cap-dependent translation initiation pathways. We show that both pathways are necessary for invadosome formation and their ECM degradation function. Finally, we highlighted a correlation between Src and eIF3h/e/d overexpression, which is associated with poor prognosis in hepatocellular carcinoma (HCC) patients and controls the ECM degradation and invasive properties of HCC cells. These findings identify Src as a major regulator of translation initiation pathways, which leads to invadosome formation, ECM degradation and tumor cell invasion. Abstract Figure Graphical abstract

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