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Published on: May 17, 2017
A Simple and Scalable Zebrafish Model of Sonic Hedgehog Medulloblastoma
Mattie J Casey1, Priya P Chan2,3, Qing Li1
1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Abstract:
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 the first zebrafish model of SHH MB using CRISPR to mutate ptch1, the primary genetic driver in human SHH MB. These tumors rapidly arise adjacent to the valvula cerebelli and resemble human SHH MB by histology and comparative genomics. In addition, ptch1-deficient MB tumors with loss of tp53 have aggressive tumor histology and significantly worse survival outcomes, comparable to human patients. The simplicity and scalability of the ptch1 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 grk3 kinase as one such target.
Insights
Researchers developed a novel zebrafish model for Sonic hedgehog (SHH) medulloblastoma (MB), the most common pediatric brain cancer. This model accurately mimics human SHH MB, including aggressive forms with TP53 mutations, aiding in the discovery of new therapeutic targets.
Area of Science:
- Neuro-oncology
- Developmental biology
- Genetics
Background:
- Medulloblastoma (MB) is the most common pediatric malignant brain tumor, with the Sonic hedgehog (SHH) subgroup (~30% of cases) exhibiting variable survival based on TP53 status.
- Current therapeutic strategies for SHH MB are limited, highlighting the need for improved preclinical models to understand tumor biology and identify novel treatment targets.
Approach:
- Developed the first zebrafish model of SHH medulloblastoma (MB) by utilizing CRISPR gene editing to mutate ptch1, a key genetic driver in human SHH MB.
- Characterized the zebrafish model for histological and genomic resemblance to human SHH MB, noting rapid tumor development adjacent to the valvula cerebelli.
- Investigated the impact of tp53 loss in ptch1-deficient zebrafish MB, observing aggressive tumor histology and significantly poorer survival outcomes.
Key Points:
- The zebrafish ptch1-mutant model recapitulates critical features of human SHH MB, including the aggressive phenotype associated with tp53 loss.
- Tumor development in this model occurs rapidly and adjacent to the valvula cerebelli, offering a tractable system for in vivo studies.
- The model's amenability to CRISPR screening facilitated the identification of grk3 kinase as a potential therapeutic target in SHH MB.
Conclusions:
- The established zebrafish model provides a scalable and effective platform for studying SHH medulloblastoma pathogenesis and for discovering new therapeutic targets.
- This model system accurately reflects the clinical heterogeneity of SHH MB, particularly the impact of TP53 status on tumor aggressiveness and survival.
- Identification of grk3 kinase underscores the utility of this model for forward genetic screens to uncover genes essential for SHH MB formation and progression.
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