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      Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration

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          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.

          Abstract

          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.

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          Most cited references130

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          Identification of c-MYC as a target of the APC pathway.

          The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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            Wnt signalling and its impact on development and cancer.

            The Wnt signalling pathway is an ancient system that has been highly conserved during evolution. It has a crucial role in the embryonic development of all animal species, in the regeneration of tissues in adult organisms and in many other processes. Mutations or deregulated expression of components of the Wnt pathway can induce disease, most importantly cancer. The first gene to be identified that encodes a Wnt signalling component, Int1 (integration 1), was molecularly characterized from mouse tumour cells 25 years ago. In parallel, the homologous gene Wingless in Drosophila melanogaster, which produces developmental defects in embryos, was characterized. Since then, further components of the Wnt pathway have been identified and their epistatic relationships have been defined. This article is a Timeline of crucial discoveries about the components and functions of this essential pathway.
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              Brain tumour cells interconnect to a functional and resistant network.

              Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Validation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Methodology
                Role: ConceptualizationRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, CA USA )
                1544-9173
                1545-7885
                17 December 2019
                December 2019
                17 December 2019
                : 17
                : 12
                : e3000545
                Affiliations
                [1 ] Instituto Cajal-CSIC, Madrid, Spain
                [2 ] Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
                [3 ] Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
                [4 ] Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany
                University of California San Diego, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                [¤]

                Current address: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, Australia

                Author information
                http://orcid.org/0000-0001-7898-962X
                http://orcid.org/0000-0002-6717-7762
                http://orcid.org/0000-0002-9589-9981
                Article
                PBIOLOGY-D-19-01582
                10.1371/journal.pbio.3000545
                6917273
                31846454
                f516c6c9-693e-41e1-8a08-bfc4ce49de3e
                © 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.

                History
                : 3 June 2019
                : 13 November 2019
                Page count
                Figures: 10, Tables: 0, Pages: 45
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100014440, Ministry of Science, Innovation and Universities;
                Award ID: IJCI-2014-19272
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100014440, Ministry of Science, Innovation and Universities;
                Award ID: BFU2015-65685P
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100014440, Ministry of Science, Innovation and Universities;
                Award ID: RYC-2012-11410
                Award Recipient :
                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.
                Categories
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                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Neurological Tumors
                Glioma
                Medicine and Health Sciences
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                Neurological Tumors
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                Biological Cultures
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