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Elife. 2018 Sep 7;7. pii: e37202. doi: 10.7554/eLife.37202.

tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish.

Author information

1
Department of Pathology, Massachusetts General Hospital Research Institute, Boston, Massachusetts.
2
Center of Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
3
Harvard Stem Cell Institute, Boston, Massachusetts.
4
Department of Molecular Medicine, Greehey Children's Cancer Research Institute, San Antonio, Texas.
5
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States.
6
Department of Pathology, University of Washington, Seattle, United States.
7
Department of Translational Research and Innovation, Université Claude Bernard Lyon, Cancer Research Center of Lyon, Lyon, France.
8
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.
#
Contributed equally

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:

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

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