Src promotes tumor cell invasion by hijacking the translation machinery

BONNARD, B.; Chatefau, A.; Dourthe, C.; Di Tommaso, S.; Dupuy, J.-W.; Mahouche, I.; Solorzano, J.; Le Bras, M.; Raymond, A.-A.; Moreau, V.; Jabouille, A.; Blangy, A.; Saltel, F.

doi:10.1101/2024.08.01.606119

bioRxiv · 10.1101/2024.08.01.606119

Src promotes tumor cell invasion by hijacking the translation machinery

BONNARD, B.·Chatefau, A.·Dourthe, C.·Di Tommaso, S.·Dupuy, J.-W.·Mahouche, I.·Solorzano, J.·Le Bras, M.·Raymond, A.-A.·Moreau, V.·Jabouille, A.·Blangy, A.·Saltel, F.

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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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/606119v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1804203org.highwire.dtl.DTLVardef@16ddae8org.highwire.dtl.DTLVardef@13ecca5org.highwire.dtl.DTLVardef@1ed685a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

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BONNARD, B., Chatefau, A., Dourthe, C., Di Tommaso, S., Dupuy, J.-W., Mahouche, I., Solorzano, J., Le Bras, M., Raymond, A.-A., Moreau, V., Jabouille, A., Blangy, A., Saltel, F.. 2024-08-01. Src promotes tumor cell invasion by hijacking the translation machinery. https://doi.org/10.1101/2024.08.01.606119

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