PUBLICATION

A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12

Authors
Burger, A., Vasilyev, A., Tomar, R., Selig, M.K., Nielsen, G.P., Peterson, R.T., Drummond, I.A., and Haber, D.A.
ID
ZDB-PUB-140127-23
Date
2014
Source
Disease models & mechanisms   7(7): 907-13 (Journal)
Registered Authors
Drummond, Iain, Peterson, Randall, Vasilyev, Aleksandr
Keywords
none
MeSH Terms
  • Disease Progression
  • Zebrafish*/embryology
  • Zebrafish*/genetics
  • Carcinogenesis/pathology
  • Notochord/drug effects
  • Notochord/metabolism*
  • Notochord/pathology
  • Notochord/ultrastructure
  • Sirolimus/pharmacology
  • Cell Line, Tumor
  • Disease Models, Animal*
  • Animals
  • Humans
  • Mutation/genetics*
  • Chordoma/embryology*
  • Chordoma/pathology*
  • Immunohistochemistry
  • Proto-Oncogene Proteins p21(ras)/genetics*
  • Animals, Genetically Modified
  • Organ Specificity/drug effects
  • Survival Analysis
(all 21)
PubMed
24311731 Full text @ Dis. Model. Mech.
Abstract

Chordoma is a malignant tumor thought to arise from remnants of the embryonic notochord with its origin in the bones of the axial skeleton. Surgical resection is the standard treatment usually in combination with radiation therapy, but neither chemotherapeutic nor targeted therapeutic approaches have demonstrated success. No animal model and only few chordoma cell lines are available for preclinical drug testing, and while no drugable genetic drivers have been identified, activation of EGFR and downstream AKT/PI3K pathways have been described. Here, we report a zebrafish model of chordoma, based on stable transgene-driven expression of HRASV12 in notochord cells during development. Extensive intra-notochordal tumor formation is evident within days of transgene expression, ultimately leading to larval death. The zebrafish tumors share characteristics of human chordoma as demonstrated by immunohistochemistry and electron microscopy. The mTORC1 inhibitor rapamycin, which has some demonstrated activity in a chordoma cell line, delays the onset of tumor formation in our zebrafish model, and improves survival of tumor-bearing fish. Consequently, the HRASV12-driven zebrafish model of chordoma may enable high-throughput screening of potential therapeutic agents for the treatment of this refractory cancer.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
fb201TgTransgenic Insertion
    io006TgTransgenic Insertion
      zf279EtTransgenic Insertion
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        Human Disease / Model
        1 - 2 of 2
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        Sequence Targeting Reagents
        No data available
        Fish
        Antibodies
        Name Type Antigen Genes Isotypes Host Organism
        Ab1-tpolyclonal
          IgGRabbit
          Ab2-krtmonoclonal
            IgG1Mouse
            Ab4-rps6polyclonal
              Rabbit
              Ab10-mapkmonoclonal
                IgGRabbit
                1 - 4 of 4
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                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                EGFPEFGEGFP
                GAL4EFGGAL4
                KALTA4EFGKALTA4
                mCherryEFGmCherry
                1 - 4 of 4
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                Mapping
                No data available