EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth
Menée à l'aide de modèles animaux (drosophiles) et de lignées cellulaires cancéreuses humaines, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation Hedgehog en coopération avec la protéine ARF6, le récepteur EGFR favorise la croissance d'une tumeur présentant une mutation activatrice du gène Ras
Multiple signalling events interact in cancer cells. Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. In turn, Egfr cooperates with Hedgehog signalling. How oncogenic Ras elicits and integrates Egfr and Hedgehog signals to drive overgrowth remains unclear. Using a Drosophila tumour model, we show that Egfr cooperates with oncogenic Ras via Arf6, which functions as a novel regulator of Hh signalling. Oncogenic Ras induces the expression of Egfr ligands. Egfr then signals through Arf6, which regulates Hh transport to promote Hh signalling. Blocking any step of this signalling cascade inhibits Hh signalling and correspondingly suppresses the growth of both, fly and human cancer cells harbouring oncogenic Ras mutations. These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf6 as a novel regulator of Hh signalling. This explains both, the puzzling requirement of Egfr in oncogenic Ras-mediated overgrowth and the cooperation between Egfr and Hedgehog.