Tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish

Myron S. Ignatius; Madeline N. Hayes; Finola E. Moore; Qin Tang; Sara P. Garcia; Patrick R. Blackburn; Kunal Baxi; Long Wang; Alexander Jin; Ashwin Ramakrishnan; Sophia Reeder; Yidong Chen; Gunnlaugur Petur Nielsen; Eleanor Y. Chen; Robert P. Hasserjian; Franck Tirode; Stephen C. Ekker; David M. Langenau

doi:10.7554/eLife.37202

Tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish

Myron S. Ignatius, Madeline N. Hayes, Finola E. Moore, Qin Tang, Sara P. Garcia, Patrick R. Blackburn, Kunal Baxi, Long Wang, Alexander Jin, Ashwin Ramakrishnan, Sophia Reeder, Yidong Chen, Gunnlaugur Petur Nielsen, Eleanor Y. Chen, Robert P. Hasserjian, Franck Tirode, Stephen C. Ekker, David M. Langenau

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germ line inactivation are predisposed to developing cancer. Here, we generated tp53 deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and an aggressive Natural Killer cell-like leukemia for which no animal model has been developed. Because the tp53 deletion was generated in syngeneic zebrafish, engraftment of fluorescent-labeled tumors could be dynamically visualized over time. Importantly, engrafted tumors shared gene expression signatures with predicted cells of origin in human tissue. Finally, we showed that tp53 ^del/del enhanced invasion and metastasis in kRAS ^G12D -induced embryonal rhabdomyosarcoma (ERMS), but did not alter the overall frequency of cancer stem cells, suggesting novel pro-metastatic roles for TP53 loss-of-function in human muscle tumors. In summary, we have developed a Li-Fraumeni zebrafish model that is amenable to large-scale transplantation and direct visualization of tumor growth in live animals.

Original language	English (US)
Article number	e37202
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.37202
State	Published - Sep 2018

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.37202

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Ignatius, M. S., Hayes, M. N., Moore, F. E., Tang, Q., Garcia, S. P., Blackburn, P. R., Baxi, K., Wang, L., Jin, A., Ramakrishnan, A., Reeder, S., Chen, Y., Nielsen, G. P., Chen, E. Y., Hasserjian, R. P., Tirode, F., Ekker, S. C., & Langenau, D. M. (2018). Tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish. eLife, 7, Article e37202. https://doi.org/10.7554/eLife.37202

Ignatius, MS, Hayes, MN, Moore, FE, Tang, Q, Garcia, SP, Blackburn, PR, Baxi, K, Wang, L, Jin, A, Ramakrishnan, A, Reeder, S, Chen, Y, Nielsen, GP, Chen, EY, Hasserjian, RP, Tirode, F, Ekker, SC & Langenau, DM 2018, 'Tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish', eLife, vol. 7, e37202. https://doi.org/10.7554/eLife.37202

@article{51aef5649ca349cf826faed2ae318c4d,

title = "Tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish",

abstract = " The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germ line inactivation are predisposed to developing cancer. Here, we generated tp53 deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and an aggressive Natural Killer cell-like leukemia for which no animal model has been developed. Because the tp53 deletion was generated in syngeneic zebrafish, engraftment of fluorescent-labeled tumors could be dynamically visualized over time. Importantly, engrafted tumors shared gene expression signatures with predicted cells of origin in human tissue. Finally, we showed that tp53 del/del enhanced invasion and metastasis in kRAS G12D -induced embryonal rhabdomyosarcoma (ERMS), but did not alter the overall frequency of cancer stem cells, suggesting novel pro-metastatic roles for TP53 loss-of-function in human muscle tumors. In summary, we have developed a Li-Fraumeni zebrafish model that is amenable to large-scale transplantation and direct visualization of tumor growth in live animals.",

author = "Ignatius, {Myron S.} and Hayes, {Madeline N.} and Moore, {Finola E.} and Qin Tang and Garcia, {Sara P.} and Blackburn, {Patrick R.} and Kunal Baxi and Long Wang and Alexander Jin and Ashwin Ramakrishnan and Sophia Reeder and Yidong Chen and Nielsen, {Gunnlaugur Petur} and Chen, {Eleanor Y.} and Hasserjian, {Robert P.} and Franck Tirode and Ekker, {Stephen C.} and Langenau, {David M.}",

note = "Publisher Copyright: {\textcopyright} Ignatius et al.",

year = "2018",

month = sep,

doi = "10.7554/eLife.37202",

language = "English (US)",

volume = "7",

journal = "eLife",

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T1 - Tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish

AU - Ignatius, Myron S.

AU - Hayes, Madeline N.

AU - Moore, Finola E.

AU - Tang, Qin

AU - Garcia, Sara P.

AU - Blackburn, Patrick R.

AU - Baxi, Kunal

AU - Wang, Long

AU - Jin, Alexander

AU - Ramakrishnan, Ashwin

AU - Reeder, Sophia

AU - Chen, Yidong

AU - Nielsen, Gunnlaugur Petur

AU - Chen, Eleanor Y.

AU - Hasserjian, Robert P.

AU - Tirode, Franck

AU - Ekker, Stephen C.

AU - Langenau, David M.

PY - 2018/9

Y1 - 2018/9

N2 - The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germ line inactivation are predisposed to developing cancer. Here, we generated tp53 deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and an aggressive Natural Killer cell-like leukemia for which no animal model has been developed. Because the tp53 deletion was generated in syngeneic zebrafish, engraftment of fluorescent-labeled tumors could be dynamically visualized over time. Importantly, engrafted tumors shared gene expression signatures with predicted cells of origin in human tissue. Finally, we showed that tp53 del/del enhanced invasion and metastasis in kRAS G12D -induced embryonal rhabdomyosarcoma (ERMS), but did not alter the overall frequency of cancer stem cells, suggesting novel pro-metastatic roles for TP53 loss-of-function in human muscle tumors. In summary, we have developed a Li-Fraumeni zebrafish model that is amenable to large-scale transplantation and direct visualization of tumor growth in live animals.

AB - The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germ line inactivation are predisposed to developing cancer. Here, we generated tp53 deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and an aggressive Natural Killer cell-like leukemia for which no animal model has been developed. Because the tp53 deletion was generated in syngeneic zebrafish, engraftment of fluorescent-labeled tumors could be dynamically visualized over time. Importantly, engrafted tumors shared gene expression signatures with predicted cells of origin in human tissue. Finally, we showed that tp53 del/del enhanced invasion and metastasis in kRAS G12D -induced embryonal rhabdomyosarcoma (ERMS), but did not alter the overall frequency of cancer stem cells, suggesting novel pro-metastatic roles for TP53 loss-of-function in human muscle tumors. In summary, we have developed a Li-Fraumeni zebrafish model that is amenable to large-scale transplantation and direct visualization of tumor growth in live animals.

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Tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish

Abstract

ASJC Scopus subject areas

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