PUBLICATION

A syngeneic spontaneous zebrafish model of tp53-deficient, EGFRvIII, and PI3KCAH1047R-driven glioblastoma reveals inhibitory roles for inflammation during tumor initiation and relapse in vivo

Authors
Weiss, A., D'Amata, C., Pearson, B.J., Hayes, M.N.
ID
ZDB-PUB-240727-17
Date
2024
Source
eLIFE   13: (Journal)
Registered Authors
D'Amata, Cass, Hayes, Madeline, Pearson, Bret, Weiss, Alex
Keywords
cancer biology, cancer variant modeling, cell biology, glioblastoma, inflammation, tumor microenvironment, zebrafish
Datasets
GEO:GSE246295
MeSH Terms
  • Brain Neoplasms*/genetics
  • Brain Neoplasms*/pathology
  • Disease Models, Animal*
  • Inflammation*/genetics
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
  • ErbB Receptors*/genetics
  • ErbB Receptors*/metabolism
  • Tumor Suppressor Protein p53*/genetics
  • Tumor Suppressor Protein p53*/metabolism
  • Tumor Microenvironment/genetics
  • Animals
  • Glioblastoma*/genetics
  • Glioblastoma*/pathology
  • Humans
  • Zebrafish*
(all 16)
PubMed
39052000 Full text @ Elife
Abstract
High-throughput vertebrate animal model systems for the study of patient-specific biology and new therapeutic approaches for aggressive brain tumors are currently lacking, and new approaches are urgently needed. Therefore, to build a patient-relevant in vivo model of human glioblastoma, we expressed common oncogenic variants including activated human EGFRvIII and PI3KCAH1047R under the control of the radial glial-specific promoter her4.1 in syngeneic tp53 loss-of-function mutant zebrafish. Robust tumor formation was observed prior to 45 days of life, and tumors had a gene expression signature similar to human glioblastoma of the mesenchymal subtype, with a strong inflammatory component. Within early stage tumor lesions, and in an in vivo and endogenous tumor microenvironment, we visualized infiltration of phagocytic cells, as well as internalization of tumor cells by mpeg1.1:EGFP+ microglia/macrophages, suggesting negative regulatory pressure by pro-inflammatory cell types on tumor growth at early stages of glioblastoma initiation. Furthermore, CRISPR/Cas9-mediated gene targeting of master inflammatory transcription factors irf7 or irf8 led to increased tumor formation in the primary context, while suppression of phagocyte activity led to enhanced tumor cell engraftment following transplantation into otherwise immune-competent zebrafish hosts. Altogether, we developed a genetically relevant model of aggressive human glioblastoma and harnessed the unique advantages of zebrafish including live imaging, high-throughput genetic and chemical manipulations to highlight important tumor-suppressive roles for the innate immune system on glioblastoma initiation, with important future opportunities for therapeutic discovery and optimizations.
Genes / Markers
Figures
Figure Gallery (14 images) / 2
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
fb105
    		Indel
    gl22TgTransgenic Insertion
      ump5TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        irf7CRISPR4-irf7CRISPR
        irf7CRISPR5-irf7CRISPR
        irf7CRISPR6-irf7CRISPR
        irf8CRISPR1-irf8CRISPR
        irf8CRISPR6-irf8CRISPR
        1 - 5 of 5
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        Fish
        No data available
        Antibodies
        Name Type Antigen Genes Isotypes Host Organism
        Ab2-aktpolyclonal
          		Rabbit
          Ab7-mapkpolyclonal
            		Rabbit
            1 - 2 of 2
            Show
            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            1 - 1 of 1
            Show
            Mapping
            No data available
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            Citation
            Weiss, A., D'Amata, C., Pearson, B.J., Hayes, M.N. (2024) A syngeneic spontaneous zebrafish model of tp53-deficient, EGFRvIII, and PI3KCAH1047R-driven glioblastoma reveals inhibitory roles for inflammation during tumor initiation and relapse in vivo. eLIFE. 13:.