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 language | English (US) |
|---|---|
| Journal | eLife |
| Volume | 7 |
| DOIs | |
| State | Published - Sep 7 2018 |
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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
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 journal › Article
}
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
C2 - 30192230
AN - SCOPUS:85056619577
VL - 7
JO - eLife
JF - eLife
SN - 2050-084X
ER -