TNFα/Grnd mediate JNK/MMPs activation during glioma progression and neurodegeneration

Glioblastoma (GB) is the most aggressive and lethal tumour of the central nervous system (CNS). GB cells proliferate rapidly and display a network of ultra-long tumour microtubes (TMs) that mediate cell to cell communication. GB TMs infiltrate into the brain, enwrap neurons and facilitate the depletion of Wingless (Wg)/WNT from the neighbouring neurons. GB cells establish a positive feedback loop including Wg signalling upregulation that activates the JNK pathway and matrix metalloproteases (MMPs), in turn, these signals promote TMs infiltration, GB progression and neuronal synapse loss and degeneration. Thus, cellular and molecular signals other than primary mutations emerge as central players of GB. Here we describe the temporal organization of the events that occur in GB. We define the progressive activation of JNK pathway signalling mediated by Grindelwald (Grnd) receptor, is caused by the ligand Eiger (Egr)/TNF produced by the healthy tissue. We propose that cellular interactions of GB with the rest of the brain is an early event that precedes GB proliferation and expansion. We conclude that non-autonomous signals facilitate GB progression and contribute to the complexity and versatility of these incurable tumours.