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

Chancellor's Office (Rochester)

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

51 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

Bibliographical note

Funding Information:
Amanda Riley Foundation Research Fellowship

Funding Information:
We thank Dr. Jim Amatruda for sharing zebrafish MPNST RNAseq sample data.Funder Grant reference number Author National Cancer Institute R24OD016761 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Jin Ashwin Ramakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau Alex’s Lemonade Stand Foundation for Childhood Cancer Myron S Ignatius Madeline N Hayes David M Langenau National Cancer Institute R00CA175184 Myron S Ignatius Kunal Baxi Lo‏ng W‏ang ‏Yidong Chen ‏‏ ‏National Cancer Cent‏er‏ RR160062 Myro‏n ‏S Ignatius‏ Kunal Baxi ‏Long Wang National Cancer Institute R01CA154923 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Ji‏n As‏hwin‏ R‏amakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau National Cancer Institute U54CA168512 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Jin Ashwin Ramakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau Rally Foundation Amanda Riley Foundation Research Fellowship Madeline N Hayes National Cancer Center R01CA211734 Madeline N Hayes Sara P Garcia Alexander Jin David M Langenau National Cancer Center R01CA21511‏8 Ma‏deli‏ne‏‏ N Hayes‏‏ S‏ara P Garcia Alexand‏er‏ Jin David M L‏an‏genau Nati‏onal Cancer ‏Institute UL1RR024150 Patrick R Blackburn National Cancer Institute GM63904 Stephen C Ekker St. Baldrick’s Foundation David M Langen‏au M‏assa‏ch‏usetts General Hospital Research Scholars Program David M Langenau The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Publisher Copyright:
© Ignatius et al.

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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{c457a4672f6c4f1bb31425c3352c6e35,

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 = "Funding Information: Amanda Riley Foundation Research Fellowship Funding Information: We thank Dr. Jim Amatruda for sharing zebrafish MPNST RNAseq sample data.Funder Grant reference number Author National Cancer Institute R24OD016761 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Jin Ashwin Ramakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau Alex{\textquoteright}s Lemonade Stand Foundation for Childhood Cancer Myron S Ignatius Madeline N Hayes David M Langenau National Cancer Institute R00CA175184 Myron S Ignatius Kunal Baxi Lo‏ng W‏ang ‏Yidong Chen ‏‏ ‏National Cancer Cent‏er‏ RR160062 Myro‏n ‏S Ignatius‏ Kunal Baxi ‏Long Wang National Cancer Institute R01CA154923 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Ji‏n As‏hwin‏ R‏amakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau National Cancer Institute U54CA168512 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Jin Ashwin Ramakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau Rally Foundation Amanda Riley Foundation Research Fellowship Madeline N Hayes National Cancer Center R01CA211734 Madeline N Hayes Sara P Garcia Alexander Jin David M Langenau National Cancer Center R01CA21511‏8 Ma‏deli‏ne‏‏ N Hayes‏‏ S‏ara P Garcia Alexand‏er‏ Jin David M L‏an‏genau Nati‏onal Cancer ‏Institute UL1RR024150 Patrick R Blackburn National Cancer Institute GM63904 Stephen C Ekker St. Baldrick{\textquoteright}s Foundation David M Langen‏au M‏assa‏ch‏usetts General Hospital Research Scholars Program David M Langenau The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: {\textcopyright} Ignatius et al.",

year = "2018",

month = sep,

doi = "10.7554/eLife.37202",

language = "English (US)",

volume = "7",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

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TY - JOUR

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.

N1 - Funding Information: Amanda Riley Foundation Research Fellowship Funding Information: We thank Dr. Jim Amatruda for sharing zebrafish MPNST RNAseq sample data.Funder Grant reference number Author National Cancer Institute R24OD016761 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Jin Ashwin Ramakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau Alex’s Lemonade Stand Foundation for Childhood Cancer Myron S Ignatius Madeline N Hayes David M Langenau National Cancer Institute R00CA175184 Myron S Ignatius Kunal Baxi Lo‏ng W‏ang ‏Yidong Chen ‏‏ ‏National Cancer Cent‏er‏ RR160062 Myro‏n ‏S Ignatius‏ Kunal Baxi ‏Long Wang National Cancer Institute R01CA154923 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Ji‏n As‏hwin‏ R‏amakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau National Cancer Institute U54CA168512 Myron S Ignatius Madeline N Hayes Finola E Moore Qin Tang Sara P Garcia Alexander Jin Ashwin Ramakrishnan Sophia Reeder Gunnlaugur Petur Nielsen Eleanor Y Chen Robert P Hasserjian David M Langenau Rally Foundation Amanda Riley Foundation Research Fellowship Madeline N Hayes National Cancer Center R01CA211734 Madeline N Hayes Sara P Garcia Alexander Jin David M Langenau National Cancer Center R01CA21511‏8 Ma‏deli‏ne‏‏ N Hayes‏‏ S‏ara P Garcia Alexand‏er‏ Jin David M L‏an‏genau Nati‏onal Cancer ‏Institute UL1RR024150 Patrick R Blackburn National Cancer Institute GM63904 Stephen C Ekker St. Baldrick’s Foundation David M Langen‏au M‏assa‏ch‏usetts General Hospital Research Scholars Program David M Langenau The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: © Ignatius et al.

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

Bibliographical note

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