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Updated: May 12, 2026
Mosaic Zebrafish Transgenesis for Functional Genomic Analysis of Candidate Cooperative Genes in Tumor Pathogenesis
Published on: March 31, 2015
Heterozygous inactivation of tsc2 enhances tumorigenesis in p53 mutant zebrafish
Seok-Hyung Kim1, Marie L Kowalski, Robert P Carson
1Department of Neurology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232, USA.
Abstract:
Tuberous sclerosis complex (TSC) is a multi-organ disorder caused by mutations of the TSC1 or TSC2 genes. A key function of these genes is to inhibit mTORC1 (mechanistic target of rapamycin complex 1) kinase signaling. Cells deficient for TSC1 or TSC2 have increased mTORC1 signaling and give rise to benign tumors, although, as a rule, true malignancies are rarely seen. In contrast, other disorders with increased mTOR signaling typically have overt malignancies. A better understanding of genetic mechanisms that govern the transformation of benign cells to malignant ones is crucial to understand cancer pathogenesis. We generated a zebrafish model of TSC and cancer progression by placing a heterozygous mutation of the tsc2 gene in a p53 mutant background. Unlike tsc2 heterozygous mutant zebrafish, which never exhibited cancers, compound tsc2;p53 mutants had malignant tumors in multiple organs. Tumorigenesis was enhanced compared with p53 mutant zebrafish. p53 mutants also had increased mTORC1 signaling that was further enhanced in tsc2;p53 compound mutants. We found increased expression of Hif1-α, Hif2-α and Vegf-c in tsc2;p53 compound mutant zebrafish compared with p53 mutant zebrafish. Expression of these proteins probably underlies the increased angiogenesis seen in compound mutant zebrafish compared with p53 mutants and might further drive cancer progression. Treatment of p53 and compound mutant zebrafish with the mTORC1 inhibitor rapamycin caused rapid shrinkage of tumor size and decreased caliber of tumor-associated blood vessels. This is the first report using an animal model to show interactions between tsc2, mTORC1 and p53 during tumorigenesis. These results might explain why individuals with TSC rarely have malignant tumors, but also suggest that cancer arising in individuals without TSC might be influenced by the status of TSC1 and/or TSC2 mutations and be potentially treatable with mTORC1 inhibitors.
Insights
Tuberous sclerosis complex (TSC) rarely causes malignancy due to TSC1/TSC2 gene function. A new zebrafish model reveals TSC2 and p53 mutations promote malignant tumors, treatable with mTORC1 inhibitors.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 genes, leading to dysregulated mTORC1 signaling and benign tumor formation.
- While TSC is associated with benign growths, the mechanisms underlying malignant transformation in cancers with increased mTOR signaling remain unclear.
- Understanding the genetic factors driving benign-to-malignant cell transition is crucial for cancer pathogenesis research.
Purpose of the Study:
- To investigate the role of TSC2 and p53 in cancer progression using a novel zebrafish model.
- To explore the interplay between TSC2, mTORC1 signaling, and p53 in tumorigenesis.
- To assess the therapeutic potential of mTORC1 inhibition in TSC-associated and related cancers.
Main Methods:
- Generation of a zebrafish model with compound heterozygous mutations in tsc2 and p53.
- Comparative analysis of tumor formation, mTORC1 signaling, and expression of angiogenesis factors (Hif1-α, Hif2-α, Vegf-c) between tsc2 heterozygous, p53 mutant, and compound tsc2;p53 mutant zebrafish.
- Treatment of zebrafish with the mTORC1 inhibitor rapamycin to evaluate tumor response.
Main Results:
- Compound tsc2;p53 mutant zebrafish developed malignant tumors across multiple organs, unlike tsc2 heterozygous mutants.
- Tumorigenesis and mTORC1 signaling were significantly enhanced in compound tsc2;p53 mutants compared to p53 mutants alone.
- Increased expression of Hif1-α, Hif2-α, and Vegf-c was observed in compound mutants, correlating with enhanced angiogenesis.
- Rapamycin treatment led to rapid tumor shrinkage and reduced tumor vascularity in both p53 and compound mutant zebrafish.
Conclusions:
- The study establishes a novel zebrafish model demonstrating the interaction between tsc2, mTORC1, and p53 in promoting malignant tumor progression.
- These findings may explain the rarity of malignancies in individuals with TSC.
- The results suggest that TSC1/TSC2 mutations could influence cancer development in non-TSC individuals and highlight the potential of mTORC1 inhibitors as a therapeutic strategy.
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