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      Extracellular Vesicles Loaded miRNAs as Potential Modulators Shared Between Glioblastoma, and Parkinson’s and Alzheimer’s Diseases

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          Abstract

          Glioblastoma (GBM) is the deadliest brain tumor. Its poor prognosis is due to cell heterogeneity, invasiveness, and high vascularization that impede an efficient therapeutic approach. In the past few years, several molecular links connecting GBM to neurodegenerative diseases (NDDs) were identified at preclinical and clinical level. In particular, giving the increasing critical role that epigenetic alterations play in both GBM and NDDs, we deeply analyzed the role of miRNAs, small non-coding RNAs acting epigenetic modulators in several key biological processes. Specific miRNAs, transported by extracellular vesicles (EVs), act as intercellular communication signals in both diseases. In this way, miRNA-loaded EVs modulate GBM tumorigenesis, as they spread oncogenic signaling within brain parenchyma, and control the aggregation of neurotoxic protein (Tau, Aβ-amyloid peptide, and α-synuclein) in NDDs. In this review, we highlight the most promising miRNAs linking GBM and NDDs playing a significant pathogenic role in both diseases.

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          Most cited references198

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          Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

          The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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            A restricted cell population propagates glioblastoma growth following chemotherapy

            Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, with a median survival of about one year 1 . This poor prognosis is due to therapeutic resistance and tumor recurrence following surgical removal. Precisely how recurrence occurs is unknown. Using a genetically-engineered mouse model of glioma, we identify a subset of endogenous tumor cells that are the source of new tumor cells after the drug, temozolomide (TMZ), is administered to transiently arrest tumor growth. A Nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumor cells. Upon arrest of tumor cell proliferation with TMZ, pulse-chase experiments demonstrate a tumor re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumor growth and combined TMZ-ganciclovir treatment impeded tumor development. These data indicate the existence of a relatively quiescent subset of endogenous glioma cells that are responsible for sustaining long-term tumor growth through the production of transient populations of highly proliferative cells.
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              An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma

              Diverse genetic, epigenetic and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the TCGA, functional approaches and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4 , EGFR and PDGFRA loci, and by mutations in the NF1 locus, that each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity and their modulation by genetic drivers.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                04 November 2020
                2020
                : 14
                : 590034
                Affiliations
                [1] 1Instituto de Investigación en Biomedicina de Buenos Aires – Consejo Nacional de Investigaciones Científicas y Técnicas – Partner Institute of the Max Planck Society , Buenos Aires, Argentina
                [2] 2Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova , Genova, Italy
                [3] 3IRCCS Ospedale Policlinico San Martino , Genova, Italy
                Author notes

                Edited by: Fabio Blandini, Neurological Institute Foundation Casimiro Mondino (IRCCS), Italy

                Reviewed by: Bernard Fioretti, University of Perugia, Italy; Simona Candiani, University of Genoa, Italy

                *Correspondence: Carolina Perez-Castro, cperezcastro@ 123456ibioba-mpsp-conicet.gov.ar

                ORCID: Laura Thomas, https://orcid.org/0000-0002-3299-4738; Carolina Perez-Castro, https://orcid.org/0000-0001-8792-7383

                This article was submitted to Cellular Neuropathology, a section of the journal Frontiers in Cellular Neuroscience

                Article
                10.3389/fncel.2020.590034
                7671965
                33328891
                2698fa17-741f-4673-b03b-23f16d2a274e
                Copyright © 2020 Thomas, Florio and Perez-Castro.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 31 July 2020
                : 07 October 2020
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 198, Pages: 21, Words: 0
                Funding
                Funded by: Agencia Nacional de Promoción Científica y Tecnológica 10.13039/501100003074
                Award ID: PICT 2018-02891
                Categories
                Neuroscience
                Review

                Neurosciences
                mirnas,extracellular vesicles,glioblastoma,alzheimer’s disease,parkinson’s disease

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