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

Cell Reports (Aug 2024)

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

Journal volume & issue: Vol. 43, no. 8
p. 114559

Abstract

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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.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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