Unknown,Transcriptomics,Genomics,Proteomics

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A mouse model of rhabdomyosarcoma originating from the adipocyte lineage

ABSTRACT: Activation of Sonic Hedgehog signaling through expression of a constitutively active Smoothened allele under control of an aP2 adipocyte-restricted transgene in mice gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human embryonal rhabdomyosarcoma with high penetrance. Conditional mouse models of embryonal rhabdomyosarcoma were created by activation of the oncogenic SmoM2 allele by both the non-muscle aP2-Cre or myotube Myogenin-Cre.

ORGANISM(S): Mus musculus

SUBMITTER: David Finkelstein

PROVIDER: E-GEOD-40359 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A mouse model of rhabdomyosarcoma originating from the adipocyte lineage.

Hatley Mark E ME Tang Wei W Garcia Matthew R MR Finkelstein David D Millay Douglas P DP Liu Ning N Graff Jonathan J Galindo Rene L RL Olson Eric N EN

Cancer cell 20121001 4

Rhabdomyosarcoma (RMS) is an aggressive skeletal muscle-lineage tumor composed of malignant myoblasts that fail to exit the cell cycle and are blocked from fusing into syncytial muscle. Rhabdomyosarcoma includes two histolopathologic subtypes: alveolar rhabdomyosarcoma, driven by the fusion protein PAX3-FOXO1 or PAX7-FOXO1, and embryonal rhabdomyosarcoma (ERMS), which is genetically heterogeneous. Here, we show that adipocyte-restricted activation of Sonic hedgehog signaling through expression o ...[more]

PMID: 23079662

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Project description:Fluorescent-labeled zebrafish RAS-induced embryonal rhabdomyosarcoma (ERMS) were created to facilitate in vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in diverse cellular compartments. Using this strategy, we have identified a molecularly distinct ERMS cell subpopulation that expresses high levels of myf5 and is enriched for ERMS-propagating potential when compared with other tumor-derived cells. Embryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that tumor-propagating potential is confined to myf5+ERMS cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ERMS cells reside within an expanded satellite cell compartment, but by late stage ERMS, myf5+cells are dynamically reorganized into distinct regions separated from differentiated tumor cells. Human ERMS also contain distinct areas of differentiated and undifferentiated cells. Time-lapse imaging revealed that myf5+ERMS cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. This finding helps explain the clinical observation that Myogenin positivity correlates with poor clinical outcome in human ERMS and suggests that differentiated tumor cells play critical roles in metastasis. One-cell stage myf5-GFP/mylz2-mCherry fluorescent transgenic zebrafish were injected with rag2-kRAS12D. A subset of animals developed ERMS. Tumor cells were transplanted into syngeneic recipient animals that lacked fluorescent reporter expression. ERMS cell subfractions were isolated from transplant animals and purified cell populations obtained following two rounds of FACS. Sorted cells were 1) analyzed by microarray/RT-PCR and 2) transplanted at limiting dilution into syngeneic animals. These experiments confirm that zebrafish ERMS contain molecularly distinct cell subfractions that express high levels of myf5-GFP and exhibit difference in gene expression when compared to other ERMS cell subtypes. All four fluorescent-labeled cell populations were analyzed (n=2 tumors total).

Dataset Information

A mouse model of rhabdomyosarcoma originating from the adipocyte lineage

Publications

A mouse model of rhabdomyosarcoma originating from the adipocyte lineage.

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