Effects of RAS on the genesis of embryonal rhabdomyosarcoma
Open accessAbstract
Embryonal rhabdomyosarcoma (ERMS) is a devastating cancer with specific features of muscle differentiation that can result from mutational activation of RAS family members. However, to date, RAS pathway activation has not been reported in a majority of ERMS patients. Here, we have created a zebrafish model of RAS-induced ERMS, in which animals develop externally visible tumors by 10 d of life. Microarray analysis and cross-species comparisons identified two conserved gene signatures found in both zebrafish and human ERMS, one associated with tumor-specific and tissue-restricted gene expression in rhabdomyosarcoma and a second comprising a novel RAS-induced gene signature. Remarkably, our analysis uncovered that RAS pathway activation is exceedingly common in human RMS. We also created a new transgenic coinjection methodology to fluorescently label distinct subpopulations of tumor cells based on muscle differentiation status. In conjunction with fluorescent activated cell sorting, cell transplantation, and limiting dilution analysis, we were able to identify the cancer stem cell in zebrafish ERMS. When coupled with gene expression studies of this cell population, we propose that the zebrafish RMS cancer stem cell shares similar self-renewal programs as those found in activated satellite cells.
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The zebrafish is a useful model for understanding normal and cancer stem cells.
“The zebrafish is a useful model for understanding normal and cancer stem cells, but analysis has been limited to embryogenesis due to the opacity of the adult fish.”
From Transparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis (2008) · cites this paper as Langenau et al., 2007
In “Identifying the cancer stem cell in zERMS” (page unavailable), the paper uses zebrafish to isolate an ERMS cancer stem cell and compares it with normal muscle satellite cells. This supports the model’s usefulness for studying cancer stem cells, but the paper does not directly establish its usefulness for studying normal stem cells. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPrior work from the authors' laboratory demonstrated that the zebrafish is a useful model for understanding the genetics of hematopoietic stem/progenitor cells and tumor stem cell biology.
“Prior work from our laboratory has demonstrated that the zebrafish is a useful model for understanding the genetics of both HSPC (Burns et al., 2005; Traver et al., 2004a”
From Transparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis (2008) · cites this paper as Langenau et al., 2007
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Cites
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Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9
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“Moreover, the mechanisms governing self-renewal are largely unknown and are now just beginning to emerge for diseases in which cancer stem cells have been identified (Krivtsov et al. 2006).”
BackgroundDhawan, J., & Rando, T. A. (2005) · Trends in Cell Biology · doi:10.1016/j.tcb.2005.10.007 · Cited by 466 · see citing works
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Transparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis
White, R. M., Sessa, A., Burke, C., Bowman, T., LeBlanc, J., Ceol, C., Bourque, C., Dovey, M., Goessling, W., Burns, C. E., et al. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2007.11.002 · Cited by 1,408 · see citing works
Self-citationAberrant AKT activation drives well-differentiated liposarcoma
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- Authors
- Langenau, D. M., Keefe, M. D., Storer, N. Y., Guyon, J. R., Kutok, J. L., Le, X., Goessling, W., Neuberg, D. S., Kunkel, L. M., & Zon, L. I.
- Affiliations
- Boston Children's Hospital (US)
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-05-17
- Volume
- 21
- Issue
- 11
- Pages
- 1382-1395
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1877750
- OpenAlex
- W2125058702
- Cited by
- 320
- References
- 3
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 21 · 2020: 11 · 2019: 18 · 2018: 12 · 2017: 11 · 2016: 27 · 2015: 22 · 2014: 18 · 2013: 22 · 2012: 18
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (R01CA103846)
- National Institute of General Medical Sciences (T32GM007753)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- embryonal rhabdomyosarcoma, RAS pathway activation, zebrafish tumor model, cancer stem cells, myogenesis, satellite cells, self-renewal, gene expression signatures, tumor heterogeneity
- MeSH terms
- Adenosine Deaminase, Animals, Cell Differentiation, Cell Transformation, Neoplastic, Cells, Cultured, DNA-Binding Proteins, Embryo, Nonmammalian, Humans, Kidney, Microinjections, Genes, ras, Biomarkers, Tumor, Zebrafish, RNA-Binding Proteins, In Situ Hybridization, Rhabdomyosarcoma, Embryonal, Muscle, Skeletal, Gene Expression Regulation, Developmental, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Animals, Genetically Modified
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