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A GFP-Tagged Gross Deletion on Chromosome 1 Causes Malignant Peripheral Nerve Sheath Tumors and Carcinomas in
Matteo Astone1, Marco Pizzi2, Margherita Peron1
1Department of Biology, University of Padova, Padova, Italy.
Abstract:
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas, characterized by complex karyotypes. The molecular bases of such malignancy are poorly understood and efficient targeted molecular therapies are currently lacking. Here we describe a novel zebrafish model of MPNSTs, represented by the transgenic mutant line Tg(-8.5nkx2.2a:GFP)ia2. ia2 homozygous animals displayed embryonic lethality by 72 hpf, while the heterozygotes develop visible tumor masses with high frequency in adulthood. Histological and immunohistochemical examination revealed aggressive tumors with either mesenchymal or epithelial features. The former (54% of the cases) arose either in the abdominal cavity, or as intrathecal/intraspinal lesions and is composed of cytokeratin-negative spindle cells with fascicular/storiform growth pattern consistent with zebrafish MPNSTs. The second histotype was composed by polygonal or elongated cells, immunohistochemically positive for the pan-cytokeratin AE1/AE3. The overall histologic and immunohistochemical features were consistent with a malignant epithelial neoplasm of possible gastrointestinal/pancreatic origin. With an integrated approach, based on microsatellite (VNTR) and STS markers, we showed that ia2 insertion, in Tg(-8.5nkx2.2a:GFP)ia2 embryos, is associated with a deletion of 15.2 Mb in the telomeric portion of chromosome 1. Interestingly, among ia2 deleted genes we identified the presence of the 40S ribosomal protein S6 gene that may be one of the possible drivers for the MPNSTs in ia2 mutants. Thanks to the peculiar features of zebrafish as animal model of human cancer (cellular and genomic similarity, transparency and prolificacy) and the GFP tag, the Tg(-8.5nkx2.2a:GFP)ia2 line provides a manageable tool to study in vivo with high frequency MPNST biology and genetics, and to identify, in concert with the existing zebrafish MPNST models, conserved relevant mechanisms in zebrafish and human cancer development.
Insights
A new zebrafish model, Tg(-8.5nkx2.2a:GFP)ia2, enables high-frequency study of malignant peripheral nerve sheath tumors (MPNSTs). This model reveals genetic deletions and potential drivers, aiding cancer research.
Area of Science:
- Oncology
- Genetics
- Zebrafish models
Background:
- Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas with poorly understood molecular drivers.
- Current targeted therapies for MPNSTs are limited, necessitating new research models.
Purpose of the Study:
- To develop and characterize a novel zebrafish model for studying MPNST biology and genetics.
- To investigate the genetic underpinnings of MPNST development in the new zebrafish model.
Main Methods:
- Generation of the transgenic zebrafish line Tg(-8.5nkx2.2a:GFP)ia2.
- Histological and immunohistochemical analysis of tumor development in adult heterozygotes.
- Microsatellite (VNTR) and STS marker analysis to identify genetic alterations associated with the ia2 insertion.
Main Results:
- Tg(-8.5nkx2.2a:GFP)ia2 heterozygotes developed high-frequency MPNSTs with mesenchymal or epithelial features.
- Mesenchymal tumors showed characteristics consistent with zebrafish MPNSTs.
- Genetic analysis revealed a 15.2 Mb deletion on chromosome 1, including the 40S ribosomal protein S6 gene, in ia2 mutants.
Conclusions:
- The Tg(-8.5nkx2.2a:GFP)ia2 zebrafish line serves as a valuable tool for in vivo MPNST research.
- The identified deletion and potential driver genes offer insights into MPNST pathogenesis.
- This model facilitates the study of conserved cancer mechanisms in zebrafish and humans.
