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 - 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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U2 - 10.7554/eLife.37202
DO - 10.7554/eLife.37202
M3 - Article
C2 - 30192230
AN - SCOPUS:85056619577
SN - 2050-084X
VL - 7
JO - eLife
JF - eLife
M1 - e37202
ER -