Effects of RAS on the genesis of embryonal rhabdomyosarcoma.
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.
Langenau
David M
DM
Stem Cell Program and Division of Hematology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Keefe
Matthew D
MD
Storer
Narie Y
NY
Guyon
Jeffrey R
JR
Kutok
Jeffery L
JL
Le
Xiuning
X
Goessling
Wolfram
W
Neuberg
Donna S
DS
Kunkel
Louis M
LM
Zon
Leonard I
LI
D000243:Adenosine Deaminase / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008845:Microinjections; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016601:RNA-Binding Proteins; D018233:Rhabdomyosarcoma, Embryonal / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; C499308:Rag2 protein, mouse; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase