Featured
-
-
Article
| Open AccessComprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants
EGFR mutations are frequent in glioblastoma and lung cancer. Here, the authors perform deep mutational scanning of EGFR, followed by a high-throughput functional screen and analysis of patient data, to identify variants with differing sensitivities to a range of EGFR tyrosine kinase inhibitors.
- Tikvah K. Hayes
- , Elisa Aquilanti
- & Matthew Meyerson
-
Article
| Open AccessTrans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma
Glioblastoma (GBM) is refractory to the chemotherapeutic genotoxin temozolomide (TMZ). Here, the authors show that GBM cells deploy RAD18-mediated Trans-Lesion Synthesis to promote error-free repair of TMZ-induced O6mG DNA lesions and avert lethality.
- Xing Cheng
- , Jing An
- & Yang Yang
-
Article
| Open AccessRepeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial
Recent work indicates that drug delivery to the brain can be improved through disruption of the blood brain barrier using low intensity pulsed ultrasound. Here, the authors report a phase I/II clinical trial investigating the combination of a nine-emitter implantable ultrasound device and carboplatin in patients with recurrent glioblastoma.
- Alexandre Carpentier
- , Roger Stupp
- & Ahmed Idbaih
-
Article
| Open AccessA clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1
In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.
- Ling Hai
- , Dirk C. Hoffmann
- & Tobias Kessler
-
Article
| Open AccessRedox-responsive polymer micelles co-encapsulating immune checkpoint inhibitors and chemotherapeutic agents for glioblastoma therapy
Immune checkpoint blockade-based immunotherapy has shown limited efficacy in patients with glioblastoma (GBM). Here the authors describe the design of redox-responsive micelles for increasing the delivery of paclitaxel and anti-PD-L1 in the brain, showing improved anti-tumor immune response in preclinical GBM models.
- Zhiqi Zhang
- , Xiaoxuan Xu
- & Shenghong Ju
-
Article
| Open AccessLogical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes
Descriptive data in biomedical research are expanding rapidly, but functional validation methods lag behind. Here, authors present Logical Synthetic cis-regulatory DNA, a framework to design reporters that mark cellular states and pathways, showcasing its applicability to complex phenotypic states.
- Carlos Company
- , Matthias Jürgen Schmitt
- & Gaetano Gargiulo
-
Article
| Open AccessPhosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma
Upregulation of GLI1 of has previously been reported in sonic hedgehog (SHH) driven medulloblastoma and basal cell carcinoma (BCC). Here, the authors find that SHH-inactivation of p38 results in stabilization of the transcription factor GLI1 via dephosphorylation at Ser937, resulting in expression of SHH genes and presenting a potential therapy strategy for medulloblastoma and BCC.
- Ling-Hui Zeng
- , Chao Tang
- & Jirong Wang
-
Article
| Open AccessInterplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas
ATRX inactivation occurs often in IDH-mutant gliomas and has been associated with immune dysfunction. Here, using preclinical models of glioma, the authors show that ATRX inactivation promotes innate immune signalling in response to double stranded RNA-based innate immune agonists, an effect that is masked in IDH-mutant tumours, presenting a therapeutic vulnerability.
- Seethalakshmi Hariharan
- , Benjamin T. Whitfield
- & David M. Ashley
-
Article
| Open AccessFunctional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance
The molecular mechanisms underlying malignant transformation of the Schwann lineage in Schwann cell tumours remain to be explored. Here, the authors suggest that NF2 inactivation leads to PAK activation leading to NF1-mutant Schwann cell tumour de-differentiation and resistance to selumetinib.
- Harish N. Vasudevan
- , Emily Payne
- & David R. Raleigh
-
Article
| Open AccessEpigenetic reprogramming shapes the cellular landscape of schwannoma
Schwannomas are regularly treated with radiotherapy, but the molecular effects on these tumours and their microenvironment remain unclear. Here, the authors show that radiotherapy can induce epigenetic reprogramming and immune infiltration in schwannomas, and develop the snARC-seq approach to analyse the epigenomic evolution at the single-cell level.
- S. John Liu
- , Tim Casey-Clyde
- & David R. Raleigh
-
Article
| Open AccessCarcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial
Oncolytic measles virus (MV) vaccine strains have shown preclinical antitumor activity against glioblastoma (GBM). Here the authors report the results of a phase 1 trial of intratumoral administration of a MV strain engineered to express the carcinoembryonic antigen in patients with recurrent GBM including assessment of viral replication and proinflammatory remodeling of the treated tumors.
- Evanthia Galanis
- , Katharine E. Dooley
- & Ian F. Parney
-
Article
| Open AccessSingle-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state
Vestibular schwannomas are benign tumours which can lead to neurological symptoms and morbidity. Here, the authors use single cell RNA-seq and ATAC-seq to identify Schwann cell subtypes in the tumour microenvironment which mimic a nerve injury phenotype.
- Thomas F. Barrett
- , Bhuvic Patel
- & Albert H. Kim
-
Article
| Open AccessCompartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage
The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory.
- David R. Ghasemi
- , Konstantin Okonechnikov
- & Kristian W. Pajtler
-
Article
| Open AccessOvercoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma
The m6A reader IGF2BP3 is upregulated in various cancer, including glioblastoma. Here the authors report that IGF2BP3 facilitates NETosis and glioma survival as well as resistance to oncolytic herpes simplex virotherapy.
- Weiwei Dai
- , Ruotong Tian
- & Minfeng Shu
-
Article
| Open AccessStabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells
Post-translational modifications including protein sumoylation is under specific regulation in glioma stem cells (GSCs). Here, the authors show that Pin1 is deubiquitinated and stabilized by USP34, which in turn promotes isomerization of Ubc9, leading to SUMO1-modified global hypersumoylation to maintain the tumorigenic capacity of GSCs.
- Qiuhong Zhu
- , Panpan Liang
- & Wenchao Zhou
-
Article
| Open AccessDeep topographic proteomics of a human brain tumour
Ultrasensitive, spatially-resolved proteomics techniques allow mapping the organisation of healthy and diseased tissues. Here, the authors develop a workflow for spatially-resolved, quantitative tissue proteomics with spatially aware statistics and clustering, with which they characterise a human atypical teratoid-rhabdoid tumour at different spatial resolutions.
- Simon Davis
- , Connor Scott
- & Roman Fischer
-
Article
| Open AccessLncRNA INHEG promotes glioma stem cell maintenance and tumorigenicity through regulating rRNA 2’-O-methylation
Long noncoding RNAs (lncRNAs) may contribute to cancer progression. Here the authors show that LncRNA INHEG modulates rRNA 2’-O-methylation and facilitates mRNA translation to promote glioma stem cell renewal and growth.
- Lihui Liu
- , Ziyang Liu
- & Runsheng Chen
-
Article
| Open AccessHigh-sensitive spatially resolved T cell receptor sequencing with SPTCR-seq
Understanding T cell behaviour in cancers is vital for improving immunotherapies. Here, the authors present spatially resolved T cell receptor sequencing (SPTCR-seq), a technology that annotates T cell receptors within the tumour ecosystem.
- Jasim Kada Benotmane
- , Jan Kueckelhaus
- & Dieter Henrik Heiland
-
Article
| Open AccessIDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma
The role of human glioma IDH1 mutations in regulation of antiviral response is unclear. Here, the authors show that D2HG produced by mutant IDH1 inhibits IFN antiviral responses in glioma cells, which confers sensitivity to oncolytic virotherapy.
- Xueqin Chen
- , Jun Liu
- & Haipeng Zhang
-
Article
| Open AccessImaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups
Atypical teratoid rhabdoid tumors (ATRT) are divided into three molecular subgroups, which could have different lineages of origin. Here, the authors use tumour imaging, multi-omics and genetically engineered mouse models to determine the anatomical region and cell lineage of origin of ATRT subtypes.
- María-Jesús Lobón-Iglesias
- , Mamy Andrianteranagna
- & Franck Bourdeaut
-
Article
| Open AccessRewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication
The integration of transcriptomics and epigenomics data helps to better understand the regulatory and topological changes in glioblastoma subtypes. Here, the authors map the promoter-enhancer interactome and regulatory landscape and show changes in promoter-enhancer interactions, chromatin accessibility, and redistribution of histone marks across four glioblastoma subtypes.
- Chaitali Chakraborty
- , Itzel Nissen
- & Silvia Remeseiro
-
Article
| Open AccessNeuropathologist-level integrated classification of adult-type diffuse gliomas using deep learning from whole-slide pathological images
Determining glioma types directly from whole-slide images (WSIs) would be of great diagnostic utility. Here, the authors develop a deep learning model to identify diffuse glioma types from WSIs according to the 2021 WHO classification across multiple cohorts and with interpretable features.
- Weiwei Wang
- , Yuanshen Zhao
- & Zhenyu Zhang
-
Article
| Open AccessSuper-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas
Hedgehog signalling is known to be linked to oncogenic proliferation. Here, the authors identify structural events as a mechanism of Hedgehog activation in over one-third of driver unknown meningiomas.
- Mark W. Youngblood
- , Zeynep Erson-Omay
- & Murat Günel
-
Article
| Open AccessNLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis
The crosstalk between innate immunity and autophagy plays a critical role in cancer. Here, the authors report that an immune receptor NLRP6 potentiates the PI3K/AKT pathway by selective degradation of p85α. The NLRP6-p85α interaction offers a potential therapeutic target for tumor treatment.
- Feng Zhi
- , Bowen Li
- & Jun Cui
-
Comment
| Open AccessBreaking barriers for glioblastoma with a path to enhanced drug delivery
Progress in treatment for glioblastoma is hindered by the blood-brain barrier (BBB). In genetic mouse models recapitulating brain invasion and abnormal angiogenesis of human glioblastoma, Cai and colleagues demonstrate that optical modulation of the BBB with nanoparticles boosts intratumoural chemotherapy concentration, prolonging survival. We discuss prospects for clinical translation of exemplary innovative techniques.
- Imran Noorani
- & Jorge de la Rosa
-
Article
| Open AccessHypoxanthine phosphoribosyl transferase 1 metabolizes temozolomide to activate AMPK for driving chemoresistance of glioblastomas
The metabolism of temozolomide (TMZ) to form methyldiazonium ions and 5-aminoimidazole-4-carboxamide (AICA) results in DNA damage, despite this, resistance frequently occurs in glioblastoma. Here, the authors demonstrate that AICA is further metabolised by HPRT1 into AICAR, which activates AMPK signalling and increases DNA damage repair. Targeting this axis in preclinical glioblastoma models sensitised tumours to TMZ.
- Jianxing Yin
- , Xiefeng Wang
- & Xu Qian
-
Article
| Open AccessDetection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas
Recurrence of meningiomas is unpredictable by current methods based on surgically removed specimens, and identification of patients likely to recur could inform treatment strategy. Here, the authors analysed DNA methylation in liquid biopsy specimens from meningioma patients to help classify recurrence risk noninvasively even before surgery.
- Grayson A. Herrgott
- , James M. Snyder
- & Houtan Noushmehr
-
Article
| Open AccessA qPCR technology for direct quantification of methylation in untreated DNA
Analysis of DNA methylation usually requires a chemical or an enzymatic pretreatment step. Here, the authors report a PCR-based technology for the detection of DNA methylation in untreated DNA, and present analytical and clinical results from methylation analysis of the MGMT promoter.
- Kamilla Kolding Bendixen
- , Maria Mindegaard
- & Rasmus Koefoed Petersen
-
Article
| Open AccessEpigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics
The role of histone deacetylases (HDACs) in glioblastoma brain tumour stem cells (BTSCs) remains to be explored. Here, pharmacological inhibition and genetic loss of function approaches show that HDAC2 leads to the maintenance of BTSC growth and self-renewal through its association with the components of the TGF-β signalling pathway.
- Ravinder K. Bahia
- , Xiaoguang Hao
- & Samuel Weiss
-
Article
| Open AccessGenomic analysis and clinical correlations of non-small cell lung cancer brain metastasis
The genomic landscape of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) remains to be explored. Here, the authors analyse a cohort of 233 patients with BM including 47 primary tumour, 42 extracranial metastatic matched samples and reveal distinct mutational patterns.
- Anna Skakodub
- , Henry Walch
- & Luke R. G. Pike
-
Article
| Open AccessOptical blood-brain-tumor barrier modulation expands therapeutic options for glioblastoma treatment
Relevant preclinical models and effective drug delivery strategies are important to advance glioblastoma (GBM) therapy. Here, the authors characterise genetically engineered mouse models that recapitulate two important GBM subtypes, and use them to show that picosecond laser stimulation of vascular-targeting gold nanoparticles can modulate blood-brain-tumour barrier permeability and expand therapeutic options for GBM.
- Qi Cai
- , Xiaoqing Li
- & Zhenpeng Qin
-
Article
| Open AccessCombining amino acid PET and MRI imaging increases accuracy to define malignant areas in adult glioma
Magnetic Resonance Imaging (MRI) is normally used to define glioma boundaries for biopsies, surgery and radiotherapy. Here, the authors show that adding FET/PET imaging improves accuracy to define malignant areas of contrast-enhancing gliomas.
- Maciej Harat
- , Józefina Rakowska
- & Bogdan Małkowski
-
Article
| Open AccessCancer cell-mitochondria hybrid membrane coated Gboxin loaded nanomedicines for glioblastoma treatment
Gboxin, an inhibitor of oxidative phosphorylation (OXPHOS), can suppress the proliferation of glioblastoma (GBM) cells. Here the authors describe the design of a cancer cell-mitochondria hybrid membrane camouflaged reactive oxygen species (ROS)-responsive nanoparticle loaded with Gboxin, showing anti-tumor responses in GBM preclinical models.
- Yan Zou
- , Yajing Sun
- & Bingyang Shi
-
Article
| Open AccessMAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas
The MAPK pathway is a key driver of pediatric low-grade gliomas (pLGG); however, response to MAPK inhibitors (MAPKi) in pLGG patients is not consistent. Here, the authors develop MAPKi sensitivity scores (MSS) to predict response to MAPKi and apply them to bulk and single-cell sequencing datasets from pLGG patients and preclinical models.
- Romain Sigaud
- , Thomas K. Albert
- & Till Milde
-
Article
| Open AccessCircular RNA encoded MET variant promotes glioblastoma tumorigenesis
MET signalling is required for glioblastoma (GBM) stem cell maintenance. Here the authors identify a circular RNA from the MET gene (circMET) that encodes a MET variant protein (MET404) and show that it can promote GBM tumorigenesis by directly activating the MET receptor independent of HGF stimulation.
- Jian Zhong
- , Xujia Wu
- & Nu Zhang
-
Article
| Open AccessSpatial cellular architecture predicts prognosis in glioblastoma
Intra-tumoral heterogeneity and cell-state plasticity contribute to the development of therapeutic resistance in glioblastoma (GBM). Here the authors use two deep learning models to predict spatial transcriptional programs and prognosis from histology images in GBM.
- Yuanning Zheng
- , Francisco Carrillo-Perez
- & Olivier Gevaert
-
Article
| Open AccessmacroH2A2 antagonizes epigenetic programs of stemness in glioblastoma
Self-renewing cells play an important role in initiation, progression, and therapy resistance in glioblastoma. Here, the authors identify histone variant macroH2A2 as a regulator of chromatin organisation resulting in the suppression of transcriptional programs of self-renewal in glioblastoma.
- Ana Nikolic
- , Francesca Maule
- & Marco Gallo
-
Article
| Open AccessType I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment
Astrocytes can influence several steps of the metastatic process in the brain. Here the authors show that type I interferon response in astrocytes facilitates brain metastasis by increasing recruitment of tumor promoting monocytic myeloid cells.
- Weili Ma
- , Maria Cecília Oliveira-Nunes
- & Qing Chen
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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