Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration.
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...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-12-01
|
| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3000545&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850240011174150144 |
|---|---|
| author | Marta Portela Varun Venkataramani Natasha Fahey-Lozano Esther Seco Maria Losada-Perez Frank Winkler Sergio Casas-Tintó |
| author_facet | Marta Portela Varun Venkataramani Natasha Fahey-Lozano Esther Seco Maria Losada-Perez Frank Winkler Sergio Casas-Tintó |
| author_sort | Marta Portela |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6d96060970784a73a2f0b1ce41db9683 |
| institution | OA Journals |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2019-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-6d96060970784a73a2f0b1ce41db96832025-08-20T02:00:59ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852019-12-011712e300054510.1371/journal.pbio.3000545Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration.Marta PortelaVarun VenkataramaniNatasha Fahey-LozanoEsther SecoMaria Losada-PerezFrank WinklerSergio Casas-TintóGlioblastoma (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.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3000545&type=printable |
| spellingShingle | Marta Portela Varun Venkataramani Natasha Fahey-Lozano Esther Seco Maria Losada-Perez Frank Winkler Sergio Casas-Tintó Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. PLoS Biology |
| title | Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. |
| title_full | Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. |
| title_fullStr | Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. |
| title_full_unstemmed | Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. |
| title_short | Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. |
| title_sort | glioblastoma cells vampirize wnt from neurons and trigger a jnk mmp signaling loop that enhances glioblastoma progression and neurodegeneration |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3000545&type=printable |
| work_keys_str_mv | AT martaportela glioblastomacellsvampirizewntfromneuronsandtriggerajnkmmpsignalingloopthatenhancesglioblastomaprogressionandneurodegeneration AT varunvenkataramani glioblastomacellsvampirizewntfromneuronsandtriggerajnkmmpsignalingloopthatenhancesglioblastomaprogressionandneurodegeneration AT natashafaheylozano glioblastomacellsvampirizewntfromneuronsandtriggerajnkmmpsignalingloopthatenhancesglioblastomaprogressionandneurodegeneration AT estherseco glioblastomacellsvampirizewntfromneuronsandtriggerajnkmmpsignalingloopthatenhancesglioblastomaprogressionandneurodegeneration AT marialosadaperez glioblastomacellsvampirizewntfromneuronsandtriggerajnkmmpsignalingloopthatenhancesglioblastomaprogressionandneurodegeneration AT frankwinkler glioblastomacellsvampirizewntfromneuronsandtriggerajnkmmpsignalingloopthatenhancesglioblastomaprogressionandneurodegeneration AT sergiocasastinto glioblastomacellsvampirizewntfromneuronsandtriggerajnkmmpsignalingloopthatenhancesglioblastomaprogressionandneurodegeneration |