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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 tp53del/del enhanced invasion and metastasis in kRASG12D-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 languageEnglish (US)
JournaleLife
Volume7
DOIs
StatePublished - Sep 7 2018

Fingerprint

Embryonal Rhabdomyosarcoma
Zebrafish
Tumors
Neoplasm Metastasis
Neoplasms
Large Granular Lymphocytic Leukemia
Hemangiosarcoma
Animals
Neoplastic Stem Cells
Germ Cell and Embryonal Neoplasms
Neurilemmoma
Tumor Suppressor Genes
Transcriptome
Germ Cells
Animal Models
Transplantation
Stem cells
Gene expression
Muscle
Muscles

Keywords

  • angiosarcoma
  • cancer biology
  • germ cell tumor
  • leukemia
  • metastasis
  • MPNST
  • rhabdomyosarcoma
  • zebrafish

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Ignatius, M. S., Hayes, M. N., Moore, F. E., Tang, Q., Garcia, S. P., Blackburn, P. R., ... Langenau, D. M. (2018). tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish. eLife, 7. https://doi.org/10.7554/eLife.37202

tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish. / Ignatius, Myron S.; Hayes, Madeline N.; Moore, Finola E.; Tang, Qin; Garcia, Sara P.; Blackburn, Patrick R.; Baxi, Kunal; Wang, Long; Jin, Alexander; Ramakrishnan, Ashwin; Reeder, Sophia; Chen, Yidong; Nielsen, Gunnlaugur Petur; Chen, Eleanor Y.; Hasserjian, Robert P.; Tirode, Franck; Ekker, Stephen C; Langenau, David M.

In: eLife, Vol. 7, 07.09.2018.

Research output: Contribution to journalArticle

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. https://doi.org/10.7554/eLife.37202
Ignatius, Myron S. ; Hayes, Madeline N. ; Moore, Finola E. ; Tang, Qin ; Garcia, Sara P. ; Blackburn, Patrick R. ; Baxi, Kunal ; Wang, Long ; Jin, Alexander ; Ramakrishnan, Ashwin ; Reeder, Sophia ; Chen, Yidong ; Nielsen, Gunnlaugur Petur ; Chen, Eleanor Y. ; Hasserjian, Robert P. ; Tirode, Franck ; Ekker, Stephen C ; Langenau, David M. / tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish. In: eLife. 2018 ; Vol. 7.
@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 tp53del/del enhanced invasion and metastasis in kRASG12D-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.",
keywords = "angiosarcoma, cancer biology, germ cell tumor, leukemia, metastasis, MPNST, rhabdomyosarcoma, zebrafish",
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.}",
year = "2018",
month = "9",
day = "7",
doi = "10.7554/eLife.37202",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

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.

PY - 2018/9/7

Y1 - 2018/9/7

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 tp53del/del enhanced invasion and metastasis in kRASG12D-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 tp53del/del enhanced invasion and metastasis in kRASG12D-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.

KW - angiosarcoma

KW - cancer biology

KW - germ cell tumor

KW - leukemia

KW - metastasis

KW - MPNST

KW - rhabdomyosarcoma

KW - zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85056619577&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056619577&partnerID=8YFLogxK

U2 - 10.7554/eLife.37202

DO - 10.7554/eLife.37202

M3 - Article

VL - 7

JO - eLife

JF - eLife

SN - 2050-084X

ER -