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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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Autores principales: Burger, Alexa, Vasilyev, Aleksandr, Tomar, Ritu, Selig, Martin K., Nielsen, G. Petur, Peterson, Randall T., Drummond, Iain A., Haber, Daniel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Limited 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073279/
https://www.ncbi.nlm.nih.gov/pubmed/24311731
http://dx.doi.org/10.1242/dmm.013128
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author Burger, Alexa
Vasilyev, Aleksandr
Tomar, Ritu
Selig, Martin K.
Nielsen, G. Petur
Peterson, Randall T.
Drummond, Iain A.
Haber, Daniel A.
author_facet Burger, Alexa
Vasilyev, Aleksandr
Tomar, Ritu
Selig, Martin K.
Nielsen, G. Petur
Peterson, Randall T.
Drummond, Iain A.
Haber, Daniel A.
author_sort Burger, Alexa
collection PubMed
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.
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spelling pubmed-40732792014-07-17 A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12 Burger, Alexa Vasilyev, Aleksandr Tomar, Ritu Selig, Martin K. Nielsen, G. Petur Peterson, Randall T. Drummond, Iain A. Haber, Daniel A. Dis Model Mech Resource Article 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. The Company of Biologists Limited 2014-07 2013-12-05 /pmc/articles/PMC4073279/ /pubmed/24311731 http://dx.doi.org/10.1242/dmm.013128 Text en © 2014. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Resource Article
Burger, Alexa
Vasilyev, Aleksandr
Tomar, Ritu
Selig, Martin K.
Nielsen, G. Petur
Peterson, Randall T.
Drummond, Iain A.
Haber, Daniel A.
A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12
title 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_short 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
topic Resource Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073279/
https://www.ncbi.nlm.nih.gov/pubmed/24311731
http://dx.doi.org/10.1242/dmm.013128
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