Defining function of wild-type and three patient specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma
- The University of Texas Health Science Center at San Antonio, United States
- Hospital for Sick Children, Canada
- University of Washington, United States
Abstract
In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153D and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153D unexpectedly also predisposes to hedgehog expressing medulloblastomas in the kRASG12D-driven ERMS-model.
Data availability
Data sets were submitted to DRYAD, available here: doi.org/10.5061/dryad.zgmsbccb6
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TP53 Zebrafish DataNCBI Gene Expression Omnibus, GSE213869.
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TP53 Zebrafish DataDryad Digital Repository, doi:10.5061/dryad.zgmsbccb6.
Article and author information
Author details
Funding
Cancer Prevention and Research Institute of Texas (Training Award,RP 170345)
- Amanda E Lipsitt
St. Baldrick's Foundation
- David S Libich
Welch Foundation
- David S Libich
University of Texas Health Science Center at San Antonio (Greehey Graduate Fellowship in Children's Health)
- Paulomi Modi
Hyundai Hope On Wheels (Young Investigator Grant)
- Amanda E Lipsitt
Max and Minnie Tomerlin Voelcker Fund (Young Investigator Award)
- Myron S Ignatius
Max and Minnie Tomerlin Voelcker Fund (Young Investigator Award)
- David S Libich
University of Texas Health Science Center at San Antonio (Cancer T32 Fellow,T32CA148724)
- Kunal Baxi
University of Texas Health Science Center at San Antonio (Translational Science TL1 Fellow,TL1TR002647)
- Kunal Baxi
Cancer Prevention and Research Institute of Texas (Scholar Grant,RR160062)
- Myron S Ignatius
University of Texas Health Science Center at San Antonio (Greehey Graduate Fellowship in Children's Health)
- Nicole Rae Hensch
National Institutes of Health (R00CA1715184)
- Peter Houghton
- Myron S Ignatius
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal studies were approved by the UT Health San Antonio Institutional Animal Care and Use Committee (IACUC) under protocol #20150015AR (mice) and #20170101AR (zebrafish). Zebrafish images were taken with specimens under tricaine anesthesia. Zebrafish tumor extraction was performed by administering high dose tricaine to minimize suffering.
Human subjects: Patient presenting with osteosarcoma signed a Consent to be part of a Repository, Epidemiology of Cancer in Children, Adolescents and Adults. In brief, this allowed for the storage of tissue, cataloging of medical information, and for research to be conducted from collected samples. The study's IRB number is HSC20080057H. Patient was informed of the risks and benefits. The umbrella study covering epidemiological study and patient-derived xenograft generation is IRB approved through UT Health San Antonio.
Copyright
© 2023, Chen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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