A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12
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 h...
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The Company of Biologists
2014-07-01
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doaj-7f6bf7432a9c451cb82eb23c13f9be212020-11-25T01:24:51ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112014-07-017790791310.1242/dmm.013128013128A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12Alexa BurgerAleksandr VasilyevRitu TomarMartin K. SeligG. Petur NielsenRandall T. PetersonIain A. DrummondDaniel A. HaberChordoma 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.http://dmm.biologists.org/content/7/7/907HRASV12CancerChordomaDrug treatmentRapamycinZebrafish |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alexa Burger Aleksandr Vasilyev Ritu Tomar Martin K. Selig G. Petur Nielsen Randall T. Peterson Iain A. Drummond Daniel A. Haber |
spellingShingle |
Alexa Burger Aleksandr Vasilyev Ritu Tomar Martin K. Selig G. Petur Nielsen Randall T. Peterson Iain A. Drummond Daniel A. Haber A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12 Disease Models & Mechanisms HRASV12 Cancer Chordoma Drug treatment Rapamycin Zebrafish |
author_facet |
Alexa Burger Aleksandr Vasilyev Ritu Tomar Martin K. Selig G. Petur Nielsen Randall T. Peterson Iain A. Drummond Daniel A. Haber |
author_sort |
Alexa Burger |
title |
A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12 |
title_short |
A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12 |
title_full |
A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12 |
title_fullStr |
A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12 |
title_full_unstemmed |
A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12 |
title_sort |
zebrafish model of chordoma initiated by notochord-driven expression of hrasv12 |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2014-07-01 |
description |
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. |
topic |
HRASV12 Cancer Chordoma Drug treatment Rapamycin Zebrafish |
url |
http://dmm.biologists.org/content/7/7/907 |
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