An adult Drosophila glioma model to highlight metabolic dysfunctions and evaluate the role of the serotonin 5‐HT7 receptor as a potential therapeutic target

Abstract

AbstractGliomas account for 50% of brain cancers and are therefore the most common brain tumors. Molecular alterations involved in adult gliomas have been identified and mainly affect tyrosine kinase receptors with amplification and/or mutation of the epidermal growth factor receptor (EGFR) and its associated signaling pathways. Several targeted therapies have been developed, but current treatments remain ineffective for glioblastomas, the most severe forms. Thus, it is a priority to identify new pharmacological targets. Drosophila glioma models established in larvae and adults are useful to identify new genes and signaling pathways involved in glioma progression. Here, we used a Drosophila glioma model in adults, to characterize metabolic disturbances associated with glioma and assess the consequences of 5‐HT7R expression on glioma development. First, by using in vivo magnetic resonance imaging, we have shown that expression of the constitutively active forms of EGFR and PI3K in adult glial cells induces brain enlargement. Then, we explored altered cellular metabolism by using high‐resolution magic angle spinning NMR and 1H‐13C heteronuclear single quantum coherence solution states. Discriminant metabolites identified highlight the rewiring of metabolic pathways in glioma and associated cachexia phenotypes. Finally, the expression of 5‐HT7R in this adult model attenuates phenotypes associated with glioma development. Collectively, this whole‐animal approach in Drosophila allowed us to provide several rapid and robust phenotype readouts, such as enlarged brain volume and glioma‐associated cachexia, as well as to determine the metabolic pathways involved in glioma genesis and finally to confirm the interest of the 5‐HT7R in the treatment of glioma.