期刊
GENES & DEVELOPMENT
卷 21, 期 11, 页码 1382-1395出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1545007
关键词
zebrafish; rhabdomyosarcoma; RAS; p53; transgenic
资金
- NCI NIH HHS [R01 CA103846, 5R01 CA103846-02] Funding Source: Medline
- NICHD NIH HHS [P30HD018655, P30 HD018655] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007753] Funding Source: Medline
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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