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

Area of Science:

• Oncology
• Genetics
• Zebrafish Models

Background:

• The TP53 tumor-suppressor gene is frequently mutated in human cancers.
• Li-Fraumeni syndrome patients with TP53 germline inactivation have a high predisposition to cancer.
• Existing animal models do not fully recapitulate the spectrum of Li-Fraumeni associated cancers.

Purpose of the Study:

• To develop a novel zebrafish model for Li-Fraumeni syndrome.
• To investigate the role of TP53 loss-of-function in cancer development and metastasis.
• To establish a platform for dynamic visualization of tumor growth and engraftment in vivo.

Main Methods:

• Generation of tp53-deleted zebrafish.
• Induction and transplantation of fluorescent-labeled tumors in syngeneic zebrafish.
• Gene expression profiling of engrafted tumors.
• Assessment of metastasis and cancer stem cell frequency in kRAS-induced embryonal rhabdomyosarcoma.

Main Results:

• tp53-deleted zebrafish spontaneously developed diverse cancers including malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and Natural Killer cell-like leukemia.
• Engrafted tumors exhibited gene expression signatures similar to human tumor cells of origin.
• TP53 loss-of-function enhanced invasion and metastasis in a kRAS-induced rhabdomyosarcoma model.
• TP53 loss did not significantly alter cancer stem cell frequency in this model.

Conclusions:

• A Li-Fraumeni zebrafish model was successfully established, recapitulating key features of the human syndrome.
• This model enables dynamic visualization of tumor progression and metastasis in live animals.
• TP53 loss-of-function plays a pro-metastatic role in certain human cancers, independent of cancer stem cell frequency.