Insulin signaling mediates neurodegeneration in glioma

Abstract

Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals in which in consequence, promotes tumor expansion at expenses of healthy tissue. The glioblastoma is the most aggressive and frequent brain tumor. This type of glioma expands and infiltrates in the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here we describe how glioblastoma produce ImpL2, an antagonist of the insulin pathway, which is regulated by the microRNA miR-8. ImpL2 targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, an early symptom of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue this synapse loss and delay the premature death caused by glioma. Therefore, signals from GB to neuron emerge as a potential field of study to prevent neurodegeneration and anti-tumoral strategies. A. (2006). Age-independent synaptogenesis by phosphoinositide 3 kinase.

Cell to cell communication mediates glioblastoma progression in Drosophila

“…Here, we investigated the mechanism by which the JNK signalling pathway is activated in GB cells. Egr activates the JNK pathway in GB cells through the specific receptor Grnd, highlighting again the contribution of communication signals between healthy brain tissue and GB cells to the progression of the disease ( Jarabo et al, 2020 ; Portela et al, 2019 ). Through transcriptional and immunofluorescence analysis of Egr in GB, we found that Egr localises mostly into the brain tissue that includes neurons and neuroblasts, and a smaller fraction of Egr is present in healthy glial cells.…”

“…Another recent study has shown that GB produces ImpL2, an antagonist of the insulin pathway that targets neighbouring neurons and causes mitochondrial disruption as well as synapse loss. Rheb overexpression in neurons, which results in activation of the PI3K pathway, prevents mitochondrial disruption as well as synapse loss and the reduction in life span caused by GB ( Jarabo et al, 2020 ).…”

JNK Pathway in CNS Pathologies

“…The glial network mediates cell-to-cell communication, and promotes the exchange of molecules between neurons and GB cells. Consequently, the JNK pathway is activated in GB cells and promotes GB progression and infiltration [ 30 , 42 , 45 ].…”

“…Consistently with the tumor chronogram, the relocalization of Egr to glial cells coincides with the synapse loss, as a previous event to tumor infiltration and proliferation. More recently, it has been shown that GB cells produce Impl2, an insulin-pathway antagonist, as a mechanism to induce neuronal alterations including mitochondrial damage, contributing to neurodegeneration and tumor progression [ 45 ]. This strategy is also mediated by JNK activity that regulates Impl2 levels of expression in GB cells [ 45 ].…”

New Cellular Dimensions on Glioblastoma Progression

“…4 Moreover, recent results from our group have established that activation of PI3K pathway in neurons by means of Rheb overexpression prevents mitochondrial defects and synapse lose, and prevents the reduction in life span caused by GB ( Figure 2). 9 Altogether, these data indicate a central role for the filopodia-like membrane protrusions (TMs in tumoral cells) in the regulation and maintenance of the signaling equilibrium between the neurons and glial cells. However, if a GB arises, the transformed glial cells expand and take advantage of the TM network to vampirize signaling molecules from the surrounding neurons to sustain tumor progression ( Figure 1), highlighting once again the critical role of the tumor microenvironment in cancer.…”