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Sequencing of canine and genetically-engineered mouse models for endotype identification of embryonal rhabdomyosarcoma

ABSTRACT: Here, we report using RNA sequencing isolated from frozen tumor samples from genetically-engineered mouse models and canine samples, as well as a preserved mouse cell culture to determine endotypes, or subtypes with distinct pathobiological mechanisms, of embryonal rhabdomyosarcoma (ERMS) and nonrhabdomyosarcoma soft tissue sarcomas (NRSTS). With an unsupervised clustering approach of DNA and RNA sequencing from mouse models, canine samples, patient-derived xenograft models, and human samples we have found several major endotypes with a wide range of putative driver mutations. This study aims to define each of the several pathological mechanisms driving tumor maintenance in these tumors in order to identify effective targeted treatments for individual patients.

ORGANISM(S): Mus musculus Canis lupus familiaris

PROVIDER: GSE142775 | GEO | 2019/12/31

REPOSITORIES: GEO

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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).

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Sequencing of canine and genetically-engineered mouse models for endotype identification of embryonal rhabdomyosarcoma

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