Src promotes tumor cell invasion by hijacking the translation machineries

The Src oncogene controls cancer cell invasiveness by promoting invadosome formation and extracellular matrix (ECM) degradation. Invadosomes are translational hotspots enriched in the eukaryotic translation initiation factor 3 (eIF3) complex that is mandatory for their maintenance. Here, we determined that Src regulates mRNA translation and controls the expression of eIF3 subunits, including eIF3h, eIF3e, and eIF3d. These subunits are crucial for invadosome formation and ECM degradation. Src also modulates both canonical eIF4E-dependent translation via the activation of the phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and the non-canonical translation mechanism through eIF3d overexpression, both of which are necessary for invadosome function. Moreover, overexpression of Src and eIF3h/e/d correlates with poor prognosis in patients with hepatocellular carcinoma (HCC), promoting ECM degradation and tumor invasiveness of HCC cells. This study identifies Src as a major regulator of translation initiation, modulating invadosome formation, ECM degradation, and tumor cell invasion.