Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration
journal contributionposted on 18.01.2021, 03:35 by Marta Portela-Esteban, V Venkataramani, Natalia Fahey-Lozano, E Seco, M Losada-Perez, F Winkler, S Casas-Tintó
© 2019 Portela et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Glioblastoma (GB) is the most lethal brain tumor, and Wingless (Wg)-related integration site (WNT) pathway activation in these tumors is associated with a poor prognosis. Clinically, the disease is characterized by progressive neurological deficits. However, whether these symptoms result from direct or indirect damage to neurons is still unresolved. Using Drosophila and primary xenografts as models of human GB, we describe, here, a mechanism that leads to activation of WNT signaling (Wg in Drosophila) in tumor cells. GB cells display a network of tumor microtubes (TMs) that enwrap neurons, accumulate Wg receptor Frizzled1 (Fz1), and, thereby, deplete Wg from neurons, causing neurodegeneration. We have defined this process as “vampirization.” Furthermore, GB cells establish a positive feedback loop to promote their expansion, in which the Wg pathway activates cJun N-terminal kinase (JNK) in GB cells, and, in turn, JNK signaling leads to the post-transcriptional up-regulation and accumulation of matrix metalloproteinases (MMPs), which facilitate TMs’ infiltration throughout the brain, TMs’ network expansion, and further Wg depletion from neurons. Consequently, GB cells proliferate because of the activation of the Wg signaling target, β-catenin, and neurons degenerate because of Wg signaling extinction. Our findings reveal a molecular mechanism for TM production, infiltration, and maintenance that can explain both neuron-dependent tumor progression and also the neural decay associated with GB.
MP holds a fellowship from the Juan de la Cierva program IJCI-2014-19272 from the Spanish MICINN. Research has been funded by grant BFU2015-65685P. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PublisherPublic Library of Science
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Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyBiologyLife Sciences & Biomedicine - Other TopicsMATRIX METALLOPROTEINASESMALIGNANT GLIOMAGENE-EXPRESSIONNERVOUS-SYSTEMMODEL SYSTEMIN-SITUJNKPATHWAYRESISTANCEPROLIFERATIONNeuronsCell Line, TumorMicrotubulesAnimalsAnimals, Genetically ModifiedHumansDrosophila melanogasterGlioblastomaBrain NeoplasmsDisease ProgressionMatrix MetalloproteinasesDrosophila ProteinsCell CommunicationMAP Kinase Signaling SystemFemaleMaleWnt1 ProteinFrizzled ReceptorsWnt Signaling PathwayHeterograftsDevelopmental Biology