Expression of the Human Serotonin 5-HT7 Receptor Rescues Phenotype Profile and Restores Dysregulated Biomarkers in a Drosophila melanogaster Glioma Model.

Gliomas are the most common primary brain tumors in adults. Significant progress has been made in recent years in identifying the molecular alterations involved in gliomas. Among them, an amplification/overexpression of the EGFR (Epidermal Growth Factor Receptor) proto-oncogene and its associated signaling pathways have been widely described. However, current treatments remain ineffective for glioblastomas, the most severe forms. Thus, the identification of other pharmacological targets could open new therapeutic avenues. We used a glioma model in Drosophila melanogaster that results from the overexpression of constitutively active forms of EGFR and PI3K specifically in glial cells. We observed hyperproliferation of glial cells that leads to an increase in brain size and lethality at the third instar larval stage. After expression of the human serotonin 5-HT7 receptor in this glioma model, we observed a decrease in larval lethality associated with the presence of surviving adults and a return to a normal morphology of brain for some Drosophila. Those phenotypic changes are accompanied by the normalization of certain metabolic biomarkers measured by High-Resolution Magic Angle Spinning NMR (HR-MAS NMR). The 5-HT7R expression in glioma also restores some epigenetic modifications and characteristic markers of the signaling pathways associated with tumor growth. This study demonstrates the role of the serotonin 5-HT7 receptor as a tumor suppressor gene which is in agreement with transcriptomic analysis obtained on human glioblastomas.

Complementary Nuclear Magnetic Resonance-Based Metabolomics Approaches for Glioma Biomarker Identification in a Drosophila melanogaster Model.

Human malignant gliomas are the most common type of primary brain tumor. Composed of glial cells and their precursors, they are aggressive and highly invasive, leading to a poor prognosis. Due to the difficulty of surgically removing tumors and their resistance to treatments, novel therapeutic approaches are needed to improve patient life expectancy and comfort. Drosophila melanogaster is a compelling genetic model to better understanding human neurological diseases owing to its high conservation in signaling pathways and cellular content of the brain. Here, glioma has been induced in Drosophila by co-activating the epidermal growth factor receptor and the phosphatidyl-inositol-3 kinase signaling pathways. Complementary nuclear magnetic resonance (NMR) techniques were used to obtain metabolic profiles in the third instar larvae brains. Fresh organs were directly studied by 1H high resolution-magic angle spinning (HR-MAS) NMR, and brain extracts were analyzed by solution-state 1H-NMR. Statistical analyses revealed differential metabolic signatures, impacted metabolic pathways, and glioma biomarkers. Each method was efficient to determine biomarkers. The highlighted metabolites including glucose, myo-inositol, sarcosine, glycine, alanine, and pyruvate for solution-state NMR and proline, myo-inositol, acetate, and glucose for HR-MAS show very good performances in discriminating samples according to their nature with data mining based on receiver operating characteristic curves. Combining results allows for a more complete view of induced disturbances and opens the possibility of deciphering the biochemical mechanisms of these tumors. The identified biomarkers provide a means to rebalance specific pathways through targeted metabolic therapy and to study the effects of pharmacological treatments using Drosophila as a model organism.