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A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1.

Nature communications | 2024

Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging and the impact on patient survival unresolved. Here, we establish a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells using a dye uptake methodology, and validate it with recording of cellular calcium epochs and clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, TM-network connectivity correlates with the mesenchymal subtype and dismal patient survival. CHI3L1 gene expression serves as a robust molecular marker of connectivity and functionally influences TM networks. The connectivity signature allows insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients' prognosis, and serves as a robust prognostic biomarker.

Pubmed ID: 38320988 RIS Download

Research resources used in this publication

Associated grants

  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: HIPO K25
  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: HIPO K32
  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: NCT 3.0 G840
  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: NCT 3.0 G840
  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: HIPO K32
  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: HIPO K32
  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: HIPO H057
  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: HIPO K25
  • Agency: Deutsches Krebsforschungszentrum (German Cancer Research Center),
    Id: HIPO K32
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation),
    Id: SFB 1389
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation),
    Id: SFB 1389
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation),
    Id: SFB 1389
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation),
    Id: SFB 1389
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation),
    Id: SFB 1389

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This is a list of tools and resources that we have found mentioned in this publication.


GATK (tool)

RRID:SCR_001876

A software package to analyze next-generation resequencing data. The toolkit offers a wide variety of tools, with a primary focus on variant discovery and genotyping as well as strong emphasis on data quality assurance. Its robust architecture, powerful processing engine and high-performance computing features make it capable of taking on projects of any size. This software library makes writing efficient analysis tools using next-generation sequencing data very easy, and second it's a suite of tools for working with human medical resequencing projects such as 1000 Genomes and The Cancer Genome Atlas. These tools include things like a depth of coverage analyzers, a quality score recalibrator, a SNP/indel caller and a local realigner. (entry from Genetic Analysis Software)

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Addgene (tool)

RRID:SCR_002037

Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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Applied Biosystems (tool)

RRID:SCR_005039

An Antibody supplier

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AppliChem (tool)

RRID:SCR_005814

An Antibody supplier

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Promega (tool)

RRID:SCR_006724

An Antibody supplier

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Thermo Fisher Scientific (tool)

RRID:SCR_008452

Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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Miltenyi Biotec (tool)

RRID:SCR_008984

An Organization portal, Antibody supplier, Service resource,

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Sigma-Aldrich (tool)

RRID:SCR_008988

American chemical, life science and biotechnology company owned by Merck KGaA. Merger of Sigma Chemical Company and Aldrich Chemical Company. Provides organic and inorganic chemicals, building blocks, reagents, advanced materials and stable isotopes for chemical synthesis, medicinal chemistry and materials science, antibiotics, buffers, carbohydrates, enzymes, forensic tools, hematology and histology, nucleotides, proteins, peptides, amino acids and their derivatives.

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Applied Biosciences (tool)

RRID:SCR_012275

Applied Biosciences is a small miority owned LLC. We specialize in hormone assays from the very small (30 g to the 5000 kg elephant) to the very large. We have a vast experience of knowledge in the endocrine field. Our experts are board certified in animal pharmacology as well as theriogenology. Combined with our Endocrinologist, there is over 75 years of experience with animal medicine and more specficially endocrinology of many animal species.

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featureCounts (tool)

RRID:SCR_012919

A read summarization program, which counts mapped reads for the genomic features such as genes and exons.

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Abcam (tool)

RRID:SCR_012931

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New England Biolabs (tool)

RRID:SCR_013517

An Antibody supplier

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Zeiss Zen Lite (tool)

RRID:SCR_023747

Software tool for basic image acquisition and analysis. Zeiss ZEN microscopy software to control of axiocam microscope cameras, image transformation and measurements, image processing, image alignment for correlative microscopy, various visualization options.

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RRID:AB_2218736

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RRID:AB_2161028

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RRID:AB_308832

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GAP43 (D9C8) Rabbit mAb (antibody)

RRID:AB_10860076

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CHI3L1 antibody (antibody)

RRID:AB_2040911

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Anti-Nestin, clone 10C2 (antibody)

RRID:AB_11211837

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BD FACSDiva Software (software resource)

RRID:SCR_001456

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ComplexHeatmap (software resource)

RRID:SCR_017270

Software package to arrange multiple heatmaps and support various annotation graphics. Used to visualize associations between different sources of data sets and to reveal potential patterns.

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HOMER (software resource)

RRID:SCR_010881

Software tools for Motif Discovery and next-gen sequencing analysis. Used for analyzing ChIP-Seq, GRO-Seq, RNA-Seq, DNase-Seq, Hi-C and numerous other types of functional genomics sequencing data sets. Collection of command line programs for unix style operating systems written in Perl and C++.

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survminer (data analysis software)

RRID:SCR_021094

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Proteomics Identifications (PRIDE) (data repository)

RRID:SCR_003411

Centralized, standards compliant, public data repository for proteomics data, including protein and peptide identifications, post-translational modifications and supporting spectral evidence. Originally it was developed to provide a common data exchange format and repository to support proteomics literature publications. This remit has grown with PRIDE, with the hope that PRIDE will provide a reference set of tissue-based identifications for use by the community. The future development of PRIDE has become closely linked to HUPO PSI. PRIDE encourages and welcomes direct user submissions of protein and peptide identification data to be published in peer-reviewed publications. Users may Browse public datasets, use PRIDE BioMart for custom queries, or download the data directly from the FTP site. PRIDE has been developed through a collaboration of the EMBL-EBI, Ghent University in Belgium, and the University of Manchester.

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ProteomeXchange (catalog)

RRID:SCR_004055

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European Genome phenome Archive (software resource)

RRID:SCR_004944

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Ingenuity Pathway Analysis (pathway analysis tool)

RRID:SCR_008653

A web-based software application that enables users to analyze, integrate, and understand data derived from gene expression, microRNA, and SNP microarrays, metabolomics, proteomics, and RNA-Seq experiments, and small-scale experiments that generate gene and chemical lists. Users can search for targeted information on genes, proteins, chemicals, and drugs, and build interactive models of experimental systems. IPA allows exploration of molecular, chemical, gene, protein and miRNA interactions, creation of custom molecular pathways, and the ability to view and modify metabolic, signaling, and toxicological canonical pathways. In addition to the networks and pathways that can be created, IPA can provide multiple layering of additional information, such as drugs, disease genes, expression data, cellular functions and processes, or a researchers own genes or chemicals of interest.

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UniProt (data or information resource)

RRID:SCR_002380

Collection of data of protein sequence and functional information. Resource for protein sequence and annotation data. Consortium for preservation of the UniProt databases: UniProt Knowledgebase (UniProtKB), UniProt Reference Clusters (UniRef), and UniProt Archive (UniParc), UniProt Proteomes. Collaboration between European Bioinformatics Institute (EMBL-EBI), SIB Swiss Institute of Bioinformatics and Protein Information Resource. Swiss-Prot is a curated subset of UniProtKB.

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Perseus (software resource)

RRID:SCR_015753

Software that supports biological and biomedical researchers in interpreting protein quantification, interaction and post-translational modification data. Perseus contains a comprehensive portfolio of statistical tools for high-dimensional omics data analysis covering normalization, pattern recognition, time-series analysis, cross-omics comparisons and multiplehypothesis testing.

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MaxQuant (software resource)

RRID:SCR_014485

A quantitative proteomics software package for analyzing large-scale mass-spectrometric data sets. It is a set of algorithms that include peak detection and scoring of peptides, mass calibration, database searches for protein identification, protein quantification, and provides summary statistics.

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Crl:CD1-Foxn1NU (organism)

RRID:IMSR_CRL:086

Mus musculus with name Crl:CD1-Foxn1NU from IMSR.

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QuantStudio 3 Real Time PCR System (instrument resource)

RRID:SCR_018712

QuantStudio 3 Real Time PCR System with 96-well 0.2-mL block. When connected to Thermo Fisher Cloud, QuantStudio 3 system provides access to your data wherever and whenever you want. Enables data accuracy and sensitivity for broad range of genomic applications.

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survival (software resource)

RRID:SCR_021137

Software R package contains core survival analysis routines, including definition of Surv objects, Kaplan-Meier and Aalen-Johansen (multi-state) curves, Cox models, and parametric accelerated failure time models.

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Genomic Data Commons Data Portal (GDC Data Portal) (data or information resource)

RRID:SCR_014514

A unified data repository of the National Cancer Institute (NCI)'s Genomic Data Commons (GDC) that enables data sharing across cancer genomic studies in support of precision medicine. The GDC supports several cancer genome programs at the NCI Center for Cancer Genomics (CCG), including The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and the Cancer Genome Characterization Initiative (CGCI). The GDC Data Portal provides a platform for efficiently querying and downloading high quality and complete data. The GDC also provides a GDC Data Transfer Tool and a GDC API for programmatic access.

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cellxgene (software resource)

RRID:SCR_021059

Software tool as interactive explorer for single cell transcriptomics datasets. Used to explore and visualize high dimensional single cell datasets in interactive way. Can visualize gene expression at level of entire dataset or particular subset of cells to help identify cell types, which can in turn help identify diseases. Enables plotting gene expression level against another gene to compare how these different genes are expressed across dataset. Open source cell visualization tool integrates with tools like SciPy and Jupyter.

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SynDB: Synapse DataBase (data or information resource)

RRID:SCR_005918

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Genotype-Tissue Expression (data repository)

RRID:SCR_013042

Project to study human gene expression and regulation in multiple tissues, providing valuable insights into mechanisms of gene regulation and its disease related perturbations. Genetic variation between individuals will be examined for correlation with differences in gene expression level to identify regions of the genome that influence whether and how much a gene is expressed. Includes initiatives: Novel Statistical Methods for Human Gene Expression Quantitative Trait Loci (eQTL) Analysis ,Laboratory, Data Analysis, and Coordinating Center (LDACC), caHUB Acquisition of Normal Tissues in Support of GTEx Project.

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Gene Expression Profiling Interactive Analysis (data access protocol)

RRID:SCR_018294

Web server for cancer and normal gene expression profiling and interactive analyses. Interactive web server for analyzing RNA sequencing expression data of tumors and normal samples from TCGA and GTEx projects, using standard processing pipeline. Provides customizable functions such as tumor or normal differential expression analysis, profiling according to cancer types or pathological stages, patient survival analysis, similar gene detection, correlation analysis and dimensionality reduction analysis.

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Chinese Glioma Genome Atlas (disease-related portal)

RRID:SCR_018802

Web application for data storage and analysis to explore brain tumors datasets from Chinese cohorts. Data portal for storage and interactive exploration of multi-dimensional functional genomic data that includes primary and recurrent glioma samples from Chinese cohorts. Allows users to browse DNA mutation profile, mRNA/microRNA expression profile and methylation profile, and to do correlation and survival analysis in specific glioma subtype.

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UCSC Xena (data access protocol)

RRID:SCR_018938

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The Cancer Genome Atlas (biomaterial supply resource)

RRID:SCR_003193

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ZEISS ZEN Microscopy Software (software resource)

RRID:SCR_013672

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ZEISS Axio Scan.Z1 Slide Scanner (instrument resource)

RRID:SCR_020927

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ggpubr (software resource)

RRID:SCR_021139

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ggplot2 (data processing software)

RRID:SCR_014601

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RRID:SCR_021140

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RRID:SCR_015246

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RRID:SCR_012802

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RRID:SCR_009803

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RRID:SCR_014966

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RRID:SCR_001622

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RRID:SCR_018168

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caret (software resource)

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ShinyGO (data access protocol)

RRID:SCR_019213

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RRID:SCR_003199

Software package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.

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RRID:SCR_016884

Software R package for statistical analysis and visualization of functional profiles for genes and gene clusters.

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RRID:SCR_010943

Software package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.

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RRID:SCR_017270

Software package to arrange multiple heatmaps and support various annotation graphics. Used to visualize associations between different sources of data sets and to reveal potential patterns.

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RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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SEURAT (software resource)

RRID:SCR_007322

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RRID:SCR_018098

Software tool to detect doublets in single-cell RNA-seq data. Software algorithm to remove doublets. Python code for identifying doublets in single-cell RNA-seq data. Framework for predicting impact of multiplets in given analysis and identifying problematic multiplets.

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RRID:SCR_015954

Software toolkit for doing various analyses of single-cell RNA-seq gene expression data, with a focus on quality control. This package facilitates pre-processing, quality control, normalization and visualization of scRNA-seq data.

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RRID:SCR_017344

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htseq-count (software resource)

RRID:SCR_011867

Script distributed with the HT-Seq Python framework for processing RNA-seq or DNA-seq data.

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Picard (software toolkit)

RRID:SCR_006525

Java toolset for working with next generation sequencing data in the BAM format.

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RRID:SCR_004463

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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RRID:SCR_005534

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Illumina HiSeq2000 Sequencing System (instrument resource)

RRID:SCR_020130

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on November 15, 2023. HiSeq 2000 sequencing system for sequencing and fastest data generation rate.

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BD FACSDiva Software (software resource)

RRID:SCR_001456

A collection of tools for flow cytometer and application setup, data acquisition, and data analysis that help streamline flow cytometry workflows. It provides features to help users integrate flow systems into new application areas, including index sorting for stem cell and single-cell applications, as well as automation protocols for high-throughput and robotic laboratories.

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NMRI-Foxn1nu (organism)

RRID:MGI:5653040

laboratory mouse with name NMRI-Foxn1nu from MGI.

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