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.
Highlights
Chordoma is a rare, slow-growing tumor that is hypothesized to arise from remnants of embryonic notochord cells
Tumorigenesis is driven by notochord-specific GFP-tagged HRASV12 expression (HRASV12 is a well-known oncogenic mutation)
As proof-of-principle, the authors demonstrate a partial response to the mTOR inhibitor rapamycin, which has shown some success in clinical trials for the treatment of chordoma
Summary
Slow-growing tumor that is hypothesized to arise from remnants of embryonic notochord cells. Complete surgical removal of the tumor whenever possible is the standard of care, usually in combination with radiation therapy, because the tumor is known to be highly chemoresistant with few proven systemic therapies available for patients with unresectable disease or distant metastases (Walcott et al, 2012). Chordoma is a type of bone cancer affecting the spine and base of the skull. These tumors are hypothesized to arise from remnants of embryonic notochord cells. The cancer is known to be highly chemoresistant, with few proven systemic therapies available for cases with unresectable disease or distant metastases. There is a pressing need for high-throughput preclinical in vivo models to direct targeted therapies in individuals with this challenging disease
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