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| Open AccessCHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity
Genetic alteration can render tumor cells resistant to immune cell-mediated killing. Here based on a genome-wide CRISPR screening, the authors show that expression of CHMP2A confers tumor cell resistance to NK cell-mediated cytotoxicity, mechanistically involving CHMP2A-dependent regulation of extracellular vesicle secretion.
- Davide Bernareggi
- , Qi Xie
- & Dan S. Kaufman
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Article
| Open AccessFatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion
Acquired radioresistance is a challenge for the cure of glioblastoma. Here, the authors show that radioresistant glioblastoma boosts mitochondrial fatty acid oxidation that fuels cell proliferation and induces immunosuppression via CD47 mediated anti-phagocytosis. Inhibition of FAO by etomoxir combined with anti-CD47 antibodies sensitizes glioblastoma to radiotherapy.
- Nian Jiang
- , Bowen Xie
- & Jian Jian Li
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Article
| Open AccessPhase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas
High-grade meningiomas have a poor prognosis with virtually no effective systemic therapies. Here, the authors report results of a phase 2 clinical trial demonstrating safety and activity of pembrolizumab, a PD-1 inhibitor, in patients with recurrent and residual high-grade meningiomas.
- Priscilla K. Brastianos
- , Albert E. Kim
- & Sandro Santagata
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Article
| Open AccessT-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10
The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness.
- Vidhya M. Ravi
- , Nicolas Neidert
- & Dieter Henrik Heiland
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Article
| Open AccessSingle-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target
Glioblastoma (GBM) is an immune cold tumour that is refractory to immunotherapy. Here, the authors identify molecular phenotypes of immune-suppressive and -promoting myeloid cells in GBM through single cell RNA sequencing and propose S100A4 as a regulator of immune suppressive T and myeloid cells in GBM.
- Nourhan Abdelfattah
- , Parveen Kumar
- & Kyuson Yun
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Article
| Open AccessPPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation
PPM1D is a known mediator of p53 signalling, and has been linked to treatment resistance in glioma. In this work, the authors utilise genomics, proteomics, and mouse models to determine the role of PPM1D in the development of diffuse midline glioma.
- Prasidda Khadka
- , Zachary J. Reitman
- & Pratiti Bandopadhayay
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Article
| Open AccessSplicing is an alternate oncogenic pathway activation mechanism in glioma
Targeting genetic drivers of high grade diffuse glioma (HGG) has not improved patient survival, suggesting the involvement of other mechanisms. Here, across cancer types, the authors identify increased alternative splicing burden in cancer drivers compared to mutation rate as an alternative mechanism for activation of oncogenic pathways such as RAS/MAPK.
- Robert Siddaway
- , Scott Milos
- & Cynthia Hawkins
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Article
| Open AccessTopographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity
Gioblastoma tumours consist of different niches defined by histology. Here, the authors use proteomics and machine learning to assign protein expression programs to these niches, and reveal that KRAS and hypoxia are associated with drug resistance.
- K. H. Brian Lam
- , Alberto J. Leon
- & Phedias Diamandis
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Article
| Open AccessAsthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
Clinical studies have suggested a reduced incidence of brain tumors, including optic gliomas, in children with asthma. Here, in a mouse model of Neurofibromatosis type 1 associated low grade optic glioma, the authors show that experimental asthma induction decreases glioma formation and growth, resulting from T cell-dependent inhibition of microglia-mediated tumor support.
- Jit Chatterjee
- , Shilpa Sanapala
- & David H. Gutmann
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Article
| Open AccessNeoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma
Immune-checkpoint blockade has shown limited benefits in patients with glioblastoma. To understand how the composition of the tumor immune microenvironment might limit clinical responses, here the authors present a high dimensional profiling of the immune landscape in patients with glioblastoma following neoadjuvant PD-1 checkpoint blockade.
- Alexander H. Lee
- , Lu Sun
- & Robert M. Prins
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Article
| Open AccessInterrogation of the microenvironmental landscape in spinal ependymomas reveals dual functions of tumor-associated macrophages
The intratumoural heterogeneity of spinal ependymomas and the role of microglia in tumour progression remain underexplored. Here, the authors perform single-cell RNA- and ATAC-sequencing data analysis of three subtypes and reveal tumour-associated macrophage subsets with distinct functional phenotypes.
- Qianqian Zhang
- , Sijin Cheng
- & Xiaoqun Wang
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Article
| Open AccessSpatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions
Neuroblastoma is a devastating tumour in children. Here, the authors analyse multi-region patient samples using genomics and transcriptomics, revealing temporal and spatial heterogeneity and questioning the reliability of single-biopsy based diagnostics.
- Karin Schmelz
- , Joern Toedling
- & Angelika Eggert
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Article
| Open AccessComparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma
The identification of patient-specific disease mechanisms and druggable targets is crucial for precision medicine in glioblastoma. Here, the authors show that comparing patients-matched glioma-initiating cells with neural stem cells enables the discovery of patient-specific mechanisms of disease and the identification of effective drugs
- Claire Vinel
- , Gabriel Rosser
- & Silvia Marino
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Article
| Open AccessGenomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases
Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.
- Sanjay M. Prakadan
- , Christopher A. Alvarez-Breckenridge
- & Alex K. Shalek
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Article
| Open AccessAn oncolytic virus expressing a full-length antibody enhances antitumor innate immune response to glioblastoma
Oncolytic herpes simplex virus-1 lyses cancer cells while increases their immunogenicity. Blocking the CD47 “don’t eat me” signal on cancer cells promotes their phagocytosis by macrophages. Authors here show that oncolytic viruses expressing anti-CD47 antibodies improve glioblastoma survival in mouse models.
- Bo Xu
- , Lei Tian
- & Jianhua Yu
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Article
| Open AccessDHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis
The glucose transporter GLUT1 is upregulated in multiple cancers and may contribute to tumour progression, but the underlying mechanisms are poorly understood. Here, the authors show that DHHC9-mediated GLUT1 palmitoylation at Cys207 is crucial for plasma membrane localisation of GLUT1 and for tumourigenesis in glioblastoma cells.
- Zhenxing Zhang
- , Xin Li
- & Xinjian Li
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Article
| Open AccessSON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
Splicing factor PTBP1 is reported to promote oncogenic functions in glioblastoma (GBM). Here the authors show splicing factor SON upregulates PTBP1 expression while supresses its paralog PTBP2 through alternative splicing and the inhibition of SON reduces GBM stemness and growth.
- Jung-Hyun Kim
- , Kyuho Jeong
- & Eun-Young Erin Ahn
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Article
| Open AccessRadiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B
Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies but their origin are still unclear. Here, the authors define the genomic, epigenetic and transcriptional landscape of 32 RIGs cases.
- Maximilian Y. Deng
- , Dominik Sturm
- & David T. W. Jones
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Article
| Open AccessComprehensive molecular characterization of pediatric radiation-induced high-grade glioma
Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. In the largest study to date, we report the results of DNA methylation profiling, RNA-Seq and genomic sequencing of 32 RIG tumors, and an in vitro drug screen in two RIG cell lines.
- John DeSisto
- , John T. Lucas Jr.
- & Adam L. Green
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Article
| Open AccessAurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma
Glioblastoma patients are treated with Aurora kinase A (AURKA) inhibitors but resistance can occur. Here, the authors show that AURKA inhibition induces metabolic reprogramming, which leads to increased mitochondrial activity and inhibition of oxidative metabolism sensitizes glioblastoma cells to AURKA inhibition.
- Trang T. T. Nguyen
- , Enyuan Shang
- & Markus D. Siegelin
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Article
| Open AccessHomozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine
The metabolite methylthioadenosine (MTA) inhibits PRMT5. Therefore, MTA accumulation due to MTA phosphorylase (MTAP) deletion has been proposed as a vulnerability for PRMT5-targeted therapy in cancer. Here, the authors show that MTA does not accumulate in MTAP-deficient cancer cells but is secreted and metabolized by MTAP-intact cells in the tumour microenvironment.
- Yasaman Barekatain
- , Jeffrey J. Ackroyd
- & Florian L. Muller
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Article
| Open AccessAgonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma
Agonistic CD40 antibodies (αCD40) have broad immunostimulatory properties, however their efficacy in glioma remains unclear. Here the authors show that αCD40 promotes the formation of tertiary lymphoid structures but does not improve survival and impairs the response to immune checkpoint blockade in murine glioma models.
- Luuk van Hooren
- , Alessandra Vaccaro
- & Anna Dimberg
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Article
| Open AccessPatient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma
Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.
- Chen He
- , Ke Xu
- & Suzanne J. Baker
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Article
| Open AccessTumor-associated hematopoietic stem and progenitor cells positively linked to glioblastoma progression
A deeper knowledge of the immune cell profile within the brain cancer tumor microenvironment (TM) could identify targets to improve immunotherapy efficacy. Here, in glioblastoma, the authors find haematopoietic stem and progenitor cells in the TM, which are associated with poor prognosis and increased immunosuppression.
- I-Na Lu
- , Celia Dobersalske
- & Igor Cima
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Article
| Open AccessSuppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance
How ROS levels are regulated in cancer stem cells and their contribution to cancer resistance is currently not clear. Here, the authors show that prohibitin regulates mitochondrial ROS production stabilizing the peroxidase PRDX3 and this accounts for radiotherapy resistance in glioma stem-like cells.
- Haohao Huang
- , Songyang Zhang
- & Jianghong Man
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Article
| Open AccessP32-specific CAR T cells with dual antitumor and antiangiogenic therapeutic potential in gliomas
Chimeric antigen receptor (CAR) T cell therapy has been proposed as a promising approach for treating glioblastoma. Here the authors show that p32 is expressed in murine and human glioma and that p32-directed CAR-T cells promote anti-tumor responses in preclinical models by targeting glioma cells and tumor derived endothelial cells.
- Liat Rousso-Noori
- , Ignacio Mastandrea
- & Dinorah Friedmann-Morvinski
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Article
| Open AccessSynergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40
Glioblastomas are generally resistant to treatment with immune checkpoint inhibitors. Here the authors show that IL6 blockade, in combination with a CD40 agonist, overcomes macrophage-mediated immunosuppression and sensitizes glioblastoma to immune checkpoint blockade in preclinical models.
- Fan Yang
- , Zhenqiang He
- & Yi Fan
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Article
| Open AccessTargeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas
Glioblastomas (GBM) are frequently resistant to immune checkpoint blockade therapy. Here the authors show that treatment with an agonistic anti-GITR antibody converts tumor infiltrating regulatory T cells to effector cells, overcoming resistance to PD1 blockade in preclinical models of GBM.
- Zohreh Amoozgar
- , Jonas Kloepper
- & Rakesh K. Jain
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Article
| Open AccessHypothalamic Rax+ tanycytes contribute to tissue repair and tumorigenesis upon oncogene activation in mice
Tanycytes contribute to the regulation of multiple hypothalamic functions. Here the authors investigate the regenerative and tumorigenic potential of adult Rax+ tanycytes in the median eminence in the context of the stem cell niche in mice.
- Wenhui Mu
- , Si Li
- & Qing-Feng Wu
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Article
| Open AccessInositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation
BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1High/CHD7Low signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.
- Sara Badodi
- , Nicola Pomella
- & Silvia Marino
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Article
| Open AccessThe white matter is a pro-differentiative niche for glioblastoma
Glioma stem cells (GSCs) retain the ability to partially differentiate, but it is unclear how the brain microenvironment may influence this response. Here the authors show that glioblastoma cells infiltrating into the white matter acquire pre-oligodendrocyte-like fate in a process that mimics myelin repair and results in tumour suppression
- Lucy J. Brooks
- , Melanie P. Clements
- & Simona Parrinello
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Article
| Open AccessThe transcriptional landscape of Shh medulloblastoma
Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.
- Patryk Skowron
- , Hamza Farooq
- & Michael D. Taylor
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Article
| Open AccessTumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma
Whether the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have a different role in glioblastoma progression and resistance to therapies is currently unclear. Here, the authors, by long-term tracking of individual glioma, demonstrate that both niches can partially compensate for each other and that glioma cells localized in both niches are resistant to radio- and chemotherapy.
- Erik Jung
- , Matthias Osswald
- & Frank Winkler
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Article
| Open AccessDual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas
Diffuse intrinsic pontine glioma (DIPG) is an almost incurable malignant childhood brain tumor. Here, the authors show that the polyamine synthetic pathway is activated in DIPG and that the dual targeting of polyamine synthesis and uptake results in prolonged survival in animal models.
- Aaminah Khan
- , Laura D. Gamble
- & David S. Ziegler
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Article
| Open AccessPRMT5 inhibition disrupts splicing and stemness in glioblastoma
The arginine methyltransferase PRMT5 is over-expressed in cancer and has a role in the maintenance of stem cells. Here, the authors show that PRMT5 inhibitors can block the growth of patient derived glioblastoma stem cell cultures in vitro and in vivo, suggesting that PRMT5 inhibition may be a useful therapeutic strategy
- Patty Sachamitr
- , Jolene C. Ho
- & Peter B. Dirks
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Article
| Open AccessVery low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy
Recurrent glioblastomas (rGBM) have dismal outcomes, but long-term survival has been observed in subsets of patients after immunotherapy. Here the authors report a positive association between low tumor mutation burden, inflammatory gene signatures, and survival after immunotherapy in rGBM patients.
- Matthias Gromeier
- , Michael C. Brown
- & David M. Ashley
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Article
| Open AccessEGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma
EGFR is frequently constitutively active in glioblastoma (GBM). Here, the authors show that EGFR induces YTHDF2 protein stabilization, which reduces cholesterol homeostasis through an RNA m6A methylation dependent molecular mechanism to promote GBM tumourigenesis.
- Runping Fang
- , Xin Chen
- & Suyun Huang
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Article
| Open AccessNon-invasive assessment of telomere maintenance mechanisms in brain tumors
Telomerase expression and the alternative lengthening of telomeres pathway are hallmarks of cancer. Here, the authors show that, in primary brain tumors, these features are correlated with metabolic signatures detectable by metabolic imaging, suggesting that they can be used to non-invasively monitor telomere maintenance in brain tumours.
- Pavithra Viswanath
- , Georgios Batsios
- & Sabrina M. Ronen
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Article
| Open AccessGlioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype
Glioblastoma is divided into four subtypes based on molecular profiling at the methylome and transcriptome level. Here the authors perform an integrative analysis of these subtypes resulting in the identification of SOX10 whose loss induces a mesenchymal phenotype and promotes tumour progression.
- Yonghe Wu
- , Michael Fletcher
- & Bernhard Radlwimmer
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Article
| Open AccessAN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion
Glioblastomas (GBMs) are highly invasive brain tumours, but the underlying mechanisms of GBM invasion are unclear. Here, the authors perform an RNA interference screen and identify AN1-Type Zinc Finger protein 3 (ZFAND3) as a regulator of GBM invasion, and find that it acts through the transcriptional regulation of invasion-related genes.
- Anne Schuster
- , Eliane Klein
- & Simone P. Niclou
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Article
| Open AccessSystemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy
The lack of effective drug delivery strategies has impaired the therapeutic progress in the treatment of glioblastoma (GBM). Here, the authors engineer synthetic protein nanoparticle based on polymerized human serum albumin equipped with the cell-penetrating peptide iRGD to deliver siRNA against STAT3 and report improved survival in a mouse model of GBM.
- Jason V. Gregory
- , Padma Kadiyala
- & Joerg Lahann
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Article
| Open AccessNeutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression
Tumour necrosis is associated with tumour aggressiveness and poor outcomes in patients with glioblastomas, but the underlying mechanisms remain poorly understood. Here, the authors show that in a xenograft mouse model of glioblastoma, tumour-infiltrating neutrophils amplify necrosis by promoting myeloperoxidase-induced tumour cell ferroptosis.
- Patricia P. Yee
- , Yiju Wei
- & Wei Li
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Article
| Open AccessCirculating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma
Non-invasive and precise methods are critical for monitoring paediatric brain cancers. Here the authors show that the molecular alterations and heterogeneity of paediatric medulloblastomas can be reliably detected in circulating tumour DNA from the cerebrospinal fluid – a routinely collected sample.
- Laura Escudero
- , Anna Llort
- & Joan Seoane
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Article
| Open AccessGlioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression
Elevated levels of interleukin-33 have been associated with poor prognosis in patients with glioma. Here the authors show that glioma-derived IL-33 modulates a pro-tumorigenic immune microenvironment by activating resident and recruiting peripheral innate immune cells.
- Astrid De Boeck
- , Bo Young Ahn
- & Donna L. Senger
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Article
| Open AccessMultiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma
Meningiomas are heterogeneous tumours. Here, the authors analysed genetic, epigenetic, and transcriptomic features across spatially-distinct meningioma samples to identify molecular programs underlying tumorigenesis that can be detected preoperatively using magnetic resonance imaging.
- Stephen T. Magill
- , Harish N. Vasudevan
- & David R. Raleigh
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Article
| Open AccessGlioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy
Intratumoural spatial heterogeneity is crucial to enhance therapeutic resistance in glioblastoma. Here, the authors show a paracrine signaling mechanism where glioblastoma-initiating cells located in the tumour edge elevate their malignancy by interaction with core-located tumour cells.
- Soniya Bastola
- , Marat S. Pavlyukov
- & Ichiro Nakano
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Article
| Open AccessWnt activation as a therapeutic strategy in medulloblastoma
The Wnt molecular subgroup of medulloblastoma is associated with better prognosis than the other molecular subgroups. Here, the authors show that activating Wnt signaling impairs tumor development and improves survival in Group 3 and Group 4 medulloblastoma preclinical models.
- Branavan Manoranjan
- , Chitra Venugopal
- & Sheila K. Singh
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Article
| Open AccessOSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation
The suppression of the receptor for oncostatin M (OSMR) can prevent glioblastoma cell growth. Here, the authors demonstrate a role for OSMR in modulating glioma stem cell respiration and its impact on resistance to ionizing radiation.
- Ahmad Sharanek
- , Audrey Burban
- & Arezu Jahani-Asl
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Article
| Open AccessMGMT genomic rearrangements contribute to chemotherapy resistance in gliomas
Chemotherapy resistance in recurrent gliomas is a large hurdle for successful therapy. Here, the authors show that some recurrent gliomas harbour O-6-methylguanine-DNA methyltransferase (MGMT) genomic rearrangements, and in vitro and in vivo these contribute to temozolomide resistance.
- Barbara Oldrini
- , Nuria Vaquero-Siguero
- & Massimo Squatrito