A simple and scalable zebrafish model of Sonic hedgehog medulloblastoma
Mattie J. Casey,
Priya P. Chan,
Qing Li,
Ju-Fen Zu,
Cicely A. Jette,
Missia Kohler,
Benjamin R. Myers,
Rodney A. Stewart
Affiliations
Mattie J. Casey
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Priya P. Chan
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA; Primary Children’s Hospital, Salt Lake City, UT 84113, USA
Qing Li
High-Throughput Genomics and Cancer Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Ju-Fen Zu
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA
Cicely A. Jette
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Missia Kohler
Department of Anatomic Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Benjamin R. Myers
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA
Rodney A. Stewart
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Corresponding author
Summary: Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ∼30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe a zebrafish model of SHH MB using CRISPR to create mutant ptch1, the primary genetic driver of human SHH MB. In these animals, tumors rapidly arise in the cerebellum and resemble human SHH MB by histology and comparative onco-genomics. Similar to human patients, MB tumors with loss of both ptch1 and tp53 have aggressive tumor histology and significantly worse survival outcomes. The simplicity and scalability of the ptch1-crispant MB model makes it highly amenable to CRISPR-based genome-editing screens to identify genes required for SHH MB tumor formation in vivo, and here we identify the gene encoding Grk3 kinase as one such target.
