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Updated: Jun 8, 2026
Mosaic Zebrafish Transgenesis for Functional Genomic Analysis of Candidate Cooperative Genes in Tumor Pathogenesis
Published on: March 31, 2015
Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers
Guangjun Zhang1, Sebastian Hoersch, Adam Amsterdam
1Department of Biology and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report that malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of mutations in either ribosomal protein (rp) genes or in p53 are highly aneuploid. Karyotyping reveals that these tumors frequently harbor near-triploid numbers of chromosomes, and they vary in chromosome number from cell to cell within a single tumor. Using array comparative genomic hybridization, we found that, as in human cancers, certain fish chromosomes are preferentially overrepresented, whereas others are underrepresented in many MPNSTs. In addition, we obtained evidence for recurrent subchromosomal amplifications and deletions that may contain genes involved in cancer initiation or progression. These focal amplifications encompassed several genes whose amplification is observed in human tumors, including met, cyclinD2, slc45a3, and cdk6. One focal amplification included fgf6a. Increasing fgf signaling via a mutation that overexpresses fgf8 accelerated the onset of MPNSTs in fish bearing a mutation in p53, suggesting that fgf6a itself may be a driver of MPNSTs. Our results suggest that the zebrafish is a useful model in which to study aneuploidy in human cancer and in which to identify candidate genes that may act as drivers in fish and potentially also in human tumors.
Insights
Zebrafish models exhibit significant aneuploidy in malignant peripheral nerve sheath tumors (MPNSTs), mirroring human cancers. This study highlights zebrafish as a valuable tool for investigating cancer aneuploidy and identifying potential cancer driver genes.
Area of Science:
- Genetics
- Oncology
- Developmental Biology
Background:
- Aneuploidy, an abnormal chromosome number, is a key feature of human cancers.
- Existing mouse cancer models often do not replicate the extensive aneuploidy observed in human tumors.
- Zebrafish are emerging as a powerful model organism for cancer research.
Purpose of the Study:
- To investigate the extent of aneuploidy in zebrafish malignant peripheral nerve sheath tumors (MPNSTs).
- To compare aneuploidy patterns in zebrafish MPNSTs with those found in human cancers.
- To identify potential driver genes involved in MPNST development in zebrafish.
Main Methods:
- Induction of MPNSTs in zebrafish through mutations in ribosomal protein (rp) genes or p53.
- Karyotyping to analyze chromosome number and variation within tumors.
- Array comparative genomic hybridization (aCGH) to detect chromosomal gains and losses.
- Analysis of subchromosomal amplifications and deletions.
Main Results:
- Zebrafish MPNSTs exhibit high levels of aneuploidy, often near-triploid, with inter-tumor and intra-tumor chromosome number variability.
- Specific zebrafish chromosomes are preferentially overrepresented or underrepresented, similar to human cancers.
- Recurrent subchromosomal amplifications and deletions were identified, including genes like met, cyclinD2, slc45a3, cdk6, and fgf6a.
- Overexpression of fgf8 accelerated MPNST onset, suggesting fgf6a as a potential driver.
Conclusions:
- Zebrafish are a relevant model for studying cancer aneuploidy, offering insights into human tumor biology.
- The identified genetic alterations and potential driver genes in zebrafish MPNSTs warrant further investigation for their role in human cancers.
- This study validates the zebrafish as a platform for discovering novel cancer-associated genes.
