Burger, A., Vasilyev, A., Tomar, R., Selig, M.K., Nielsen, G.P., Peterson, R.T., Drummond, I.A., and Haber, D.A. (2014) A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12. Disease models & mechanisms. 7(7):907-13.
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.