Cell to cell communication is an early event in glioblastoma

Abstract

Glioblastoma (GB) is a type of brain tumour that involves the transformation of glial cells. This is the most aggressive and lethal tumour of the central nervous system and currently there are not efficient treatments. In GB, glial cells display a network of membrane projections (cytonemes) which mediate cell to cell communication. Under pathological conditions like GB, cytonemes transform into ultra-long tumour microtubes (TMs) that infiltrate into the brain, enwrap neurons and deplete wingless (Wg)/WNT from the neighbouring healthy tissue. GB cells establish a positive feedback loop including Wg signalling, JNK and matrix metalloproteases (MMP) required for GB progression and neuronal synapse loss and degeneration. Frizzled1 receptor mediates Wg signalling upregulation which is required for JNK activation in GB. Consequently, MMPs are upregulated and facilitate TMs infiltration in the brain, hence GB TMs network expands and mediate further Wg depletion to close the loop. Thus, cellular signals other than primary mutations emerge as a central feature of GB which correlates with a poor prognosis in patients and animal models. Here we describe the molecular mechanisms that regulate TMs production, infiltration and maintenance, in a Drosophila model of GB. The contribution of the bi-directional signals between healthy tissue (neurons) and GB cells, mediate the progression of the disease. JNK pathway signalling mediated by Grindelwald (Grnd) receptor is activated by the ligand Eiger (Egr)/TNFα secreted by the neurons surrounding the GB.Then, MMPs are secreted to facilitate TM progression and GB dissemination. Here we show that the coordination among different signals facilitate GB progression and contribute to the complexity and versatility of these incurable tumours.