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- Title
Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration.
- Authors
Portela, Marta; Venkataramani, Varun; Fahey-Lozano, Natasha; Seco, Esther; Losada-Perez, Maria; Winkler, Frank; Casas-Tintó, Sergio
- Abstract
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. Glioblastoma is the most lethal brain tumor and is characterized by progressive neurological deficits. However, whether these symptoms result from direct or indirect damage to neurons is still unresolved. This study shows that glioblastoma cells compete with healthy neurons for survival, depleting the signaling molecule Wg and causing neurodegeneration.
- Subjects
GLIOBLASTOMA multiforme; NEURONS; MATRIX metalloproteinases; BRAIN tumors; NEURODEGENERATION; TRABECULAR meshwork (Eye)
- Publication
PLoS Biology, 2019, Vol 17, Issue 12, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000545