RT Journal Article
T1 Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration
A1 Portela, Marta
A1 Venkataramani, Varun
A1 Fahey-Lozano, Natasha
A1 Seco, Esther
A1 Losada Pérez, María De La Paloma
A1 Winkler, Frank
A1 Casas-Tintó, Sergio
AB 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.
PB Public Library of Science
SN 1544-9173
YR 2019
FD 2019-12-17
LK https://hdl.handle.net/20.500.14352/107503
UL https://hdl.handle.net/20.500.14352/107503
LA eng
NO Portela, M., Venkataramani, V., Fahey-Lozano, N., Seco, E., Losada-Perez, M., Winkler, F., & Casas-Tintó, S. (2019). Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. PLOS Biology, 17(12), e3000545. https://doi.org/10.1371/journal.pbio.3000545
NO Ministerio de Economía y Competitividad (España)
DS Docta Complutense
RD 21 abr 2025