Seminars

Activation of Ras GTPases by mutations is one of the most frequent oncogenic events in human cancers, but no effective targeted therapies currently exist for patients with Ras-driven tumours. Three major down-stream pathways are stimulated by Ras proteins: MAP kinases, PI3 kinases and Ral GTPases (RalA and RalB). Ral proteins are key players in the coordination between membrane trafficking and actin polymerization. Unexpectedly, we found that RalB pathway is the major driver of Ras-dependent invasiveness, with MAPK and PI3K contributions being dispensable. We developed a novel optogenetic approach to assess the cause-effect relationships in the Ras-Ral signaling axis with a spatial-temporal resolution. Light-controlled local activation of Ral promotes, via its effector exocyst, the recruitment of the Wave Regulatory Complex (WRC) at the leading edge, where WRC stimulates actin polymerization and protrusion formation. Illumination-driven Ral activation per se is sufficient to trigger cell invasion. The potential inhibition by drugs of this RalB-driven pro-invasive mechanism definitely deserves further investigations.