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Article
| Open AccessReversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma
Noradrenergic and mesenchymal cell states have been proposed in neuroblastoma, but their contributions to the tumour are not clearly understood. Here, the authors used in vitro and in vivo models, as well as single-cell RNA-seq, to characterise noradrenergic and mesenchymal cells and their phenotypic plasticity in neuroblastoma.
- Cécile Thirant
- , Agathe Peltier
- & Isabelle Janoueix-Lerosey
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Article
| Open AccessRe-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states
Glioblastoma (GBM) cells can infiltrate into the tumour microenvironment (TME) and contribute to recurrence. Here, the authors analyse primary and recurrent GBMs and their TME using single-nucleus and spatial transcriptomics, revealing tissue states defined by the combinations of neoplastic and non-neoplastic cells, which could be therapeutic targets.
- Osama Al-Dalahmah
- , Michael G. Argenziano
- & Peter Canoll
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Article
| Open AccessMetabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma
The molecular mechanisms underlying MYC overexpression in group 3 medulloblastoma remain to be explored. Here, the authors highlight the involvement of the mitochondrial pyruvate carrier- SOD2 signalling pathway in the regulation of MYC protein abundance.
- Emma Martell
- , Helgi Kuzmychova
- & Tanveer Sharif
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Article
| Open Access3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma
Ependymoma is a tumor of the brain or spinal cord with the two most common and aggressive types mainly occurring in children. Here the authors employ 3D genomics and epigenomics to reveal targets for aggressive ependymoma tumors in children.
- Konstantin Okonechnikov
- , Aylin Camgöz
- & Lukas Chavez
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Article
| Open AccessSema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma
Wnt signaling is dysregulated in glioblastoma (GBM). Here the authors show that Semaphorin 3C drives Wnt signaling through Rac1-dependent β-catenin nuclear accumulation and that dual blockade of Semaphorin 3C and Wnt pathway reduces the growth of GBM in vivo.
- Jing Hao
- , Xiangzi Han
- & Jennifer S. Yu
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Article
| Open AccessCAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy
Neutrophil-mediated drug delivery has been investigated as a therapeutic approach for brain tumors. Here the authors report the anti-tumor activity of chlorotoxin-directed CAR neutrophils delivering chemodrug-loaded nanoparticles in preclinical glioblastoma models.
- Yun Chang
- , Xuechao Cai
- & Xiaoping Bao
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Article
| Open AccessMonocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma
Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.
- Zhihong Chen
- , Nishant Soni
- & Dolores Hambardzumyan
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Article
| Open AccessRewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation
The dysregulation of the m6A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m6A reader YTHDF2, resulting in the initiation of gliomas.
- An Xu
- , Mo Liu
- & Dung-Fang Lee
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Article
| Open AccessSTING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma
Glioblastoma is an immunologically cold tumour, with poor CD8 + T cell infiltration and enrichment in immunosuppressive tumour-associated myeloid cells. Here, the authors generate a bispecific lipid nanoparticle targeting CD47 and PD-L1, combined with a STING agonist, to promote anti-tumour immunity.
- Peng Zhang
- , Aida Rashidi
- & Maciej S. Lesniak
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Article
| Open AccessCheckpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade
Immunotherapies have shown limited efficacy in patients with glioma. Here, based on an in vivo kinome knockout CRISPR screen, the authors show that checkpoint kinase 2 promotes CD8 T cell immune evasion and that its depletion or inhibition improve survival and response to PD1/PDL1 blockade in preclinical glioma models.
- Crismita Dmello
- , Junfei Zhao
- & Adam M. Sonabend
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Article
| Open AccessIGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis
Glioblastoma stem-like cells (GSCs) contribute to therapeutic resistance and recurrence of glioblastomas. Here the authors show that Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) promotes GSCs invasion.
- Weiwei Lin
- , Rui Niu
- & Jinlong Yin
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Article
| Open AccessQuinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis
The upstream metabolism of tryptophan has been described as a metabolic node in glioblastoma. Here the authors show that the downstream metabolism of tryptophan, resulting in the accumulation of quinolinate in glioblastoma, contributes to pro-tumorigenic immune suppressive activation of macrophages.
- Pravin Kesarwani
- , Shiva Kant
- & Prakash Chinnaiyan
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Article
| Open AccessBET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas
Bromodomain and extraterminal proteins (BET) are reported as targets for anticancer therapy. Here, the authors report the final results of a phase I clinical trial of the BET inhibitor trotabresib in patients with solid tumours and diffuse large B-cell lymphoma.
- Victor Moreno
- , Maria Vieito
- & Irene Braña
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Article
| Open AccessARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
CDKN2A loss and p53 mutations are rare in MYC-driven Group 3 medulloblastomas (MBs). Here the authors generated a transgenic mouse model of Group 3 MB by MYC overexpression and show that MYC suppresses ARF to drive tumorigenesis.
- Oliver J. Mainwaring
- , Holger Weishaupt
- & Fredrik J. Swartling
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Article
| Open AccessDietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism
Diet intervention is emerging as an option to improve cancer therapy. Here, the authors show that a diet with restrictive cysteine and methionine synergizes with a ferroptosis inducer to increase cell death and survival in glioma preclinical models.
- Pavan S. Upadhyayula
- , Dominique M. Higgins
- & Peter Canoll
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Article
| Open AccessSpatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas
The spatial organisation of diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) remains to be investigated. Here, the authors integrate short-read and long-read spatial profiling of DMG and GBM to identify regulatory programs and cellular ecosystems in distinct glioma niches.
- Yanming Ren
- , Zongyao Huang
- & Yuan Wang
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Article
| Open AccessA nitric-oxide driven chemotactic nanomotor for enhanced immunotherapy of glioblastoma
The blood-brain barrier represents a hurdle for the delivery of therapeutics in brain tumor tissues. Here the authors describe the design of a nitric oxide-driven nanomotor loaded with the glycolysis inhibitor lonidamine, breaking through the blood-brain barrier and eliciting anti-tumor immune responses in preclinical models of glioblastoma.
- Huan Chen
- , Ting Li
- & Mimi Wan
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Article
| Open AccessT cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles
Glioblastoma is a highly aggressive, and also the most common, brain tumour type in adults. Here, the authors generate a nanoparticle encapsulating the TLR7/8 agonist, R848, which induces tumour regression in mice by reprogramming myeloid cells independently of T and NK cells.
- Verena Turco
- , Kira Pfleiderer
- & Michael Platten
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Article
| Open AccessFGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells
Glioblastoma is an aggressive type of cancer with poor patient prognosis. Here, the authors show that T cells armed with an FGL2-specific scFV can induce antitumour responses mediated by tissue-resident memory T cells in the brain.
- Qingnan Zhao
- , Jiemiao Hu
- & Shulin Li
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Article
| Open AccessLoss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability
Group 3 medulloblastomas (MBs) have the worst prognosis amongst the subtypes of MBs and are associated with MYC amplifications. Here the authors identify that mutations in CTDNEP1 cause MYC activation, amplification, and genomic instability in this subtype of MBs.
- Zaili Luo
- , Dazhuan Xin
- & Q. Richard Lu
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Article
| Open AccessProteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms
The proteogenomic landscape of diffuse gliomas remains to be explored. Here, the authors perform proteogenomic characterisation of diffuse gliomas, investigate the functional role of genomic alterations and suggest three proteomic subgroups.
- Yunzhi Wang
- , Rongkui Luo
- & Chen Ding
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Article
| Open AccessCellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma
Senescence can have beneficial and detrimental impact on cancer progression depending on the cellular context. Here the authors show that NRF2 regulates the senescence phenotype in malignant cells which consequently contribute to glioblastoma progression.
- Rana Salam
- , Alexa Saliou
- & Isabelle Le Roux
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Article
| Open AccessReprogramming systemic and local immune function to empower immunotherapy against glioblastoma
Glioblastoma (GBM) is characterized by local and systemic immunosuppression, showing limited responses to immunotherapies. Here the authors describe the design of a nanoplatform composed of the lymphopenia alleviating agent cannabidiol and the lymphocyte recruiting cytokine LIGHT, promoting anti-tumor immune responses in GBM preclinical models.
- Songlei Zhou
- , Yukun Huang
- & Jun Chen
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Article
| Open AccessFederated learning enables big data for rare cancer boundary detection
Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.
- Sarthak Pati
- , Ujjwal Baid
- & Spyridon Bakas
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Article
| Open AccessDecoding molecular programs in melanoma brain metastases
Melanoma brain metastases (MBM) show heterogeneous therapeutic response determined by incompletely understood mechanisms. Here, the authors use a multi-OMICS approach and targeted sequencing (TargetSeq) to decipher programs that may define molecular subsets of MBM and their response to therapy.
- Josefine Radke
- , Elisa Schumann
- & Torben Redmer
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Article
| Open AccessNear infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma
Effective drug accumulation in deep glioblastoma multiforme (GBM) lesions remains challenging due to the blood brain barrier. Here, the authors develop a biomimetic nanogel system activated by near infrared irradiation and show high efficacy in orthotopic GBM and GBM stem cells-bearing mouse models.
- Dongya Zhang
- , Sidan Tian
- & Liang Luo
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Article
| Open AccessEpigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas
While recurrence is frequent in ependymoma, the underlying molecular mechanisms remain to be explored. Here, the authors investigate epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses over 13 years and identify distinct patterns of DNA methylation.
- Sibo Zhao
- , Jia Li
- & Xiao-Nan Li
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Article
| Open AccessSpatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival
Characterisation of molecular heterogeneity in glioblastoma would improve patient stratification. Here, the authors integrate spatial proteomics and clinical data from glioblastoma patients and identify 3 molecular groups and a 5-protein signature that was associated with survival.
- Marie Duhamel
- , Lauranne Drelich
- & Michel Salzet
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Article
| Open AccessNeuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma
Responses to immune checkpoint blockade (ICB) in patients with glioblastoma are limited. Here the authors show that Calmodulin-Dependent Kinase Kinase 2 (CaMKK2) is expressed in tumor associated macrophages and neurons and is associated with resistance to ICB in preclinical models of glioblastoma.
- William H. Tomaszewski
- , Jessica Waibl-Polania
- & John H. Sampson
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Article
| Open AccessBlood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma
Tumor-associated macrophages are believed to promote tumour progression and to hamper immune therapy in gliomas. Here authors identify a distinct population of macrophages within the glioblastoma immune microenvironment with antitumour properties and clearly distinguishable phenotypes and gene expression patterns from tumour promoting macrophages.
- Hyun-Jin Kim
- , Jang Hyun Park
- & Heung Kyu Lee
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Article
| Open AccessP300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells
Therapeutic stress induces phenotypic plasticity in glioma stem cells although the mechanisms underlying this remain poorly understood. Here, the authors show that P300 mediates the radiation-induced vascular-like conversion of glioma stem cells to promote tumor recurrence.
- Sree Deepthi Muthukrishnan
- , Riki Kawaguchi
- & Harley I. Kornblum
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Article
| Open AccessDNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival
Glucocorticoids, such as dexamethasone, are used as anti-inflammatory and immunosuppressive drugs, however patients may exhibit resistance or side effects. Here the authors propose that a dexamethasone related neutrophil-specific DNA methylation index can be used as a marker of glucocorticoid exposure and response and as a prognostic factor in brain tumor survival.
- J. K. Wiencke
- , Annette M. Molinaro
- & Karl T. Kelsey
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Article
| Open AccessAngiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells
Glioma stem-like cells (GSCs) exhibit plasticity during proneural-to-mesenchymal transition. Here the authors show that extracellular vesicles from endothelial cells can promote this transition of GSCs through activation of MMPs and NFkB, and inactivation of NOTCH.
- Lata Adnani
- , Jordan Kassouf
- & Janusz Rak
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Article
| Open AccessConserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer
TERT promoter mutations are the most common noncoding alterations in cancers, although some remain to be characterised. Here, the authors identify TERT promoter duplications across seven cancer types that are functionally equivalent to well-known hotspot TERT mutations and are clonal in a multifocal glioblastoma patient.
- Carter J. Barger
- , Abigail K. Suwala
- & Joseph F. Costello
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Article
| Open AccessBacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy
Different blood-brain barrier permeable systems, such as bacteria loaded with chemotherapy, have been proposed to treat glioblastoma. Here, the authors generate bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles to eliminate bacteria-infected glioblastoma cells and induce an anti-tumour immune response upon photothermal therapy.
- Rong Sun
- , Mingzhu Liu
- & Yao He
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Article
| Open AccessSingle cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma
The components of the glioma immune microenvironment and their roles in promoting tumourigenesis remain poorly understood. Here, the use of single-cell RNA sequencing and multiplexed tissue-imaging in adult and pediatric high-grade gliomas reveals the activity and spatial organization of the immunomodulatory purinergic signaling pathway.
- Shannon Coy
- , Shu Wang
- & Sandro Santagata
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Article
| Open AccessA slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness
Quiescent cancer stem cells have been particularly associated to chemoresistance. Here, the authors show that a slowcycling subpopulation in high-grade glioma patients can invade the brain to promote tumourigenesis.
- Francesco Antonica
- , Lucia Santomaso
- & Luca Tiberi
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Article
| Open AccessCircular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands
Glioblastoma (GBM) is a highly aggressive brain tumor, frequently resistant to therapies, including natural killer (NK) cell based immunotherapy. Here, the authors show that the circular RNA EZH2 is highly expressed in GBM and encodes the peptide EZH2-92aa, whose expression is associated with inhibition of NK cell cytotoxicity.
- Jian Zhong
- , Xuesong Yang
- & Nu Zhang
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Article
| Open AccessDNA methylation-based epigenetic signatures predict somatic genomic alterations in gliomas
No clinical assay currently exists to classify glioma tumours based on gene expression. Here, the authors develop a DNA methylation-based classifier, Unified Diagnostic Pipeline (UniD) that identifies genomic alterations and gene expression subtypes of gliomas.
- Jie Yang
- , Qianghu Wang
- & Erik P. Sulman
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Article
| Open AccessEngineered biomimetic nanoparticles achieve targeted delivery and efficient metabolism-based synergistic therapy against glioblastoma
Targeting cancer-associated metabolism is evolving as a promising approach for cancer therapy. Here, the authors generate cancer cell-membrane encapsulated nanoparticles to induce cell cycle arrest and cytotoxicity in lactate-high cancer cells, reducing tumourigensis in glioblastoma cell-line and patient-derived models.
- Guihong Lu
- , Xiaojun Wang
- & Wei Wei
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Article
| Open AccessA phase I/II study of triple-mutated oncolytic herpes virus G47∆ in patients with progressive glioblastoma
G47Δ is a third-generation, triple-mutated oncolytic HSV-1 that has demonstrated anti-tumor efficacy in preclinical studies. Here the authors report the results of a phase I/II study of G47Δ in patients with recurrent or progressive glioblastoma.
- Tomoki Todo
- , Yasushi Ino
- & Minoru Tanaka
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Article
| Open AccessA brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours
The link between neural development and tumourigenesis in adult glioma remains unclear. Here, the authors monitor the developmental stages of Sox2 + /− stem cells from a mouse model using single-cell RNA sequencing and suggest the acquisition of embryonic-like states in the adult glioma development.
- Akram A. Hamed
- , Daniel J. Kunz
- & Peter B. Dirks
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Article
| Open AccessPro-inflammatory cytokines mediate the epithelial-to-mesenchymal-like transition of pediatric posterior fossa ependymoma
The molecular mechanisms underlying ependymoma tumorigenesis remain poorly understood. Here, single cell analysis of posterior fossa primary tumours and distal metastases highlights the role of pro-inflammatory cytokines in promoting epithelial-to-mesenchymal-transition.
- Rachael G. Aubin
- , Emma C. Troisi
- & Pablo G. Camara
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Article
| Open AccessSpatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression
It is essential to improve our understanding of the features that influence aggressiveness and invasion in high grade gliomas (HGG). Here, the authors characterize dynamic anatomical structures in HGG called oncostreams, which are associated with tumor growth and are regulated by COL1A1.
- Andrea Comba
- , Syed M. Faisal
- & Pedro R. Lowenstein
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Article
| Open AccessTarget receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells
The use of cell-based therapies may be helpful in eradicating cancer cells. Here, the authors generate bifunctional mesenchymal stem cells and demonstrate their therapeutic efficacy in glioblastoma patient-derived models.
- Deepak Bhere
- , Sung Hugh Choi
- & Khalid Shah
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Article
| Open AccessNeuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1
Neuronal activity is emerging as a driver of nervous system tumors. Here, the authors show in mouse models of Neurofibromatosis-1 (NF1) that Nf1 mutations differentially drive both central and peripheral nervous system tumor growth in mice through reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function.
- Corina Anastasaki
- , Juan Mo
- & David H. Gutmann
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Article
| Open AccessThe genomic and transcriptional landscape of primary central nervous system lymphoma
Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.
- Josefine Radke
- , Naveed Ishaque
- & Frank L. Heppner
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Article
| Open AccessZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage
Improved treatment of glioblastoma (GBM) can be achieved by inducing differentiation of glioblastoma stem cells (GSCs). Here, the authors show that zinc finger protein 117 (ZNF117) is a regulator of GSC differentiation via Notch signaling through interaction with JAG2, and can be targeted for therapy.
- Jun Liu
- , Xiaoying Wang
- & Jiangbing Zhou
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Article
| Open AccessAstroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes
Astroblastoma (AB) is an uncommon brain tumour and its origin remains unknown. Here, the authors perform integrative molecular analysis of 35 AB-like tumours and provide evidence that these arise in the context of epigenetic and genetic changes in neural progenitors occurring during brain development.
- Norman L. Lehman
- , Nathalie Spassky
- & Akshitkumar M. Mistry