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Dis Model Mech. 2014 Jul;7(7):907-13. doi: 10.1242/dmm.013128. Epub 2013 Dec 5.

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

Author information

1
Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
2
Division of Nephrology, Massachusetts General Hospital, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Department of Biomedical Sciences, NYIT COM, Old Westbury, New York, NY 11568, USA.
3
Division of Nephrology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
4
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
5
Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA. Broad Institute, Cambridge, MA 02142, USA.
6
Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Haber@helix.mgh.harvard.edu.

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, although no druggable 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 could enable high-throughput screening of potential therapeutic agents for the treatment of this refractory cancer.

KEYWORDS:

Cancer; Chordoma; Drug treatment; HRASV12; Rapamycin; Zebrafish

PMID:
24311731
PMCID:
PMC4073279
DOI:
10.1242/dmm.013128
[Indexed for MEDLINE]
Free PMC Article

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