Glioblastoma (GBM), a very aggressive and incurable tumor, often results from constitutive activation of EGFR (epidermal growth factor receptor) and of PI3K (phosphoinositide 3-kinase). To understand the role of autophagy in the pathogenesis of glial tumors in vivo, we used an established Drosophila melanogaster model of glioma based on overexpression in larval glial cells of an active human EGFR and of the PI3K homolog Dp110. Interestingly, the resulting hyperplastic glia expresses high levels of ref(2)P (refractory to Sigma P), the Drosophila homolog of p62/SQSTM1. However, cellular clearance of autophagic cargoes appears inhibited upstream of autophagosome formation. Remarkably, downregulation of subunits of the vacuolar-H+-ATPase (V-ATPase) prevents overgrowth, reduces PI3K 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 VATPase could represent a therapeutic target against GBM.

V-ATPase controls tumor growth and autophagy in a Drosophila model of gliomagenesis / M. Formica, A.M. Storaci, I. Bertolini, V. Vaira, T. Vaccari. - (2020 Jul). [10.1101/2020.07.20.211565]

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

Miriam Formica;Alessandra Storaci;Irene Bertolini;Valentina Vaira;Thomas Vaccari
2020-07

Abstract

Glioblastoma (GBM), a very aggressive and incurable tumor, often results from constitutive activation of EGFR (epidermal growth factor receptor) and of PI3K (phosphoinositide 3-kinase). To understand the role of autophagy in the pathogenesis of glial tumors in vivo, we used an established Drosophila melanogaster model of glioma based on overexpression in larval glial cells of an active human EGFR and of the PI3K homolog Dp110. Interestingly, the resulting hyperplastic glia expresses high levels of ref(2)P (refractory to Sigma P), the Drosophila homolog of p62/SQSTM1. However, cellular clearance of autophagic cargoes appears inhibited upstream of autophagosome formation. Remarkably, downregulation of subunits of the vacuolar-H+-ATPase (V-ATPase) prevents overgrowth, reduces PI3K 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 VATPase could represent a therapeutic target against GBM.
autophagy; cancer model; fruit fly; glioblastoma; lysosomes; neurospheres; ref(2)P; VATPase
Settore BIO/13 - Biologia Applicata
https://www.biorxiv.org/content/10.1101/2020.07.20.211565v1
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/767171
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