title: A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12.
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.
authors: Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors: Alexa
authors: A
authors: Burger
authors: 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.
authors: Aleksandr
authors: A
authors: Vasilyev
authors: Division of Nephrology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors: Ritu
authors: R
authors: Tomar
authors: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Martin K
authors: MK
authors: Selig
authors: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: G Petur
authors: GP
authors: Nielsen
authors: 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.
authors: Randall T
authors: RT
authors: Peterson
authors: Division of Nephrology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors: Iain A
authors: IA
authors: Drummond
authors: Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Haber@helix.mgh.harvard.edu.
authors: Daniel A
authors: DA
authors: Haber
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D002817:Chordoma / Q000196:embryology* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation / Q000235:genetics*; D009672:Notochord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009928:Organ Specificity / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020123:Sirolimus / Q000494:pharmacology; D016019:Survival Analysis; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus
keywords: Cancer; Chordoma; Drug treatment; HRASV12; Rapamycin; Zebrafish