V-ATPase controls tumor growth and autophagy in a Drosophila model of gliomagenesis

Glioblastoma (GBM), a very aggressive and incurable tumor, often results from constitutive activation of EGFR (epidermal growth factor receptor) and of phosphoinositide 3-kinase (PI3K). To understand the role of autophagy in the pathogenesis of glial tumors <i>in vivo</i>, we used an established <i>Drosophila melanogaster</i> model of glioma based on overexpression in larval glial cells of an active human <i>EGFR</i> and of the PI3K homolog <i>Pi3K92E/Dp110</i>. Interestingly, the resulting hyperplastic glia express high levels of key components of the lysosomal-autophagic compartment, including vacuolar-type H⁺-ATPase (V-ATPase) subunits and ref(2)P (refractory to Sigma P), the <i>Drosophila</i> homolog of SQSTM1/p62. However, cellular clearance of autophagic cargoes appears inhibited upstream of autophagosome formation. Remarkably, downregulation of subunits of V-ATPase, of <i>Pdk1</i>, or of the Tor (Target of rapamycin) complex 1 (TORC1) component <i>raptor</i> prevents overgrowth and normalize ref(2)P levels. In addition, downregulation of the V-ATPase subunit <i>VhaPPA1-1</i> reduces Akt and Tor-dependent signaling and restores clearance. Consistent with evidence in flies, neurospheres from patients with high V-ATPase subunit expression show inhibition of autophagy. Altogether, our data suggest that autophagy is repressed during glial tumorigenesis and that V-ATPase and MTORC1 components acting at lysosomes could represent therapeutic targets against GBM.