eLife: 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 

Abstract

The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germline 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.

 

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