Synaptic components are required for glioblastoma progression in Drosophila

Abstract

Glioblastoma (GB) is the most aggressive, lethal and frequent primary brain tumor. It originates from glial cells and is characterized by rapid expansion through infiltration. GB cells interact with the microenvironment and healthy surrounding tissues, mostly neurons and vessels. GB cells project tumor microtubes (TMs) contact with neurons, and exchange signaling molecules related to Wingless/WNT, JNK, Insulin or Neuroligin-3 pathways. This cell to cell communication promotes GB expansion and neurodegeneration. Moreover, healthy neurons form glutamatergic functional synapses with GB cells which facilitate GB expansion and premature death in mouse GB xerograph models. Targeting signaling and synaptic components of GB progression may become a suitable strategy against glioblastoma. In a Drosophila GB model, we have determined the post-synaptic nature of GB cells with respect to neurons, and the contribution of post-synaptic genes expressed in GB cells to tumor progression. In addition, we document the presence of intratumoral synapses between GB cells, and the functional contribution of pre-synaptic genes to GB calcium dependent activity and expansion. Finally, we explore the relevance of synaptic genes in GB cells to the lifespan reduction caused by GB advance. Our results indicate that both presynaptic and postsynaptic proteins play a role in GB progression and lethality.

SV2B/miR-34a/miR-128 axis as prognostic biomarker in glioblastoma multiforme

“…It acts as a primary calcium (Ca 2+ ) sensor in the mechanisms of neurotransmission and hormone secretion, and it plays a crucial role in processes triggered by Ca 2+ for secretion 28 . Given the involvement of SYT1 and its calcium-binding protein product, this gene has appeared in GBM hub oncogene nodes alongside SV2B 29 , 30 . Moreover, a larger scale analysis of glioblastoma and normal brain tissue samples obtained from the TCGA and GEO databases revealed that SYT1 was one of the core genes associated with GBM progression among the 552 differentially expressed genes in that analysis 31 .…”

Membranome Similarity between Glioblastoma Multiforme Cell Lines and Primary Tumors

“…A certain number of these underexpressed genes were associated with synaptic signaling. Indeed, recent evidence suggests that gliomas engage in synaptic communication and this neural integration may be crucial for glioma progression [29,30]. It has also been shown that neuron-glioma interactions are bidirectional and gliomas induce hyperexcitability through secretion of synaptogenic factors, and reducing surrounding inhibitory interneurons [30][31][32][33].…”

“…Indeed, recent evidence suggests that gliomas engage in synaptic communication and this neural integration may be crucial for glioma progression [29,30]. It has also been shown that neuron-glioma interactions are bidirectional and gliomas induce hyperexcitability through secretion of synaptogenic factors, and reducing surrounding inhibitory interneurons [30][31][32][33]. Additionally, cell lines' membranome displayed decreased expression of genes related to ion transport and homeostasis.…”

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

“…These two models have been widely used to identify new genes and signaling pathways involved in glioma progression. [41][42][43][44][45] Among the genes possibly involved in the progression of glioma, our recent data demonstrated the role of the serotonin 5-HT 7 receptor (5-HT 7 R) in a larval Drosophila model of glioma. 46 The human 5-HT 7 R expression in this animal model reduced larval lethality and partially restored dysregulated biomarkers.…”

“…The second model, established by Chi et al 40 , allowed to induce glioma development specifically at the adult stage. These two models have been widely used to identify new genes and signaling pathways involved in glioma progression 41–45 …”