Distinct and Overlapping Sarcoma Subtypes Initiated from Muscle Stem and Progenitor Cells

Rebecca D Dodd; Jordan M Blum; Leonor Añó; Zhizhong Li; David Van Mater; Brian D Bennett; Mohit Sachdeva; Irina Lagutina; Minsi Zhang; Jeffrey K Mito; Leslie G Dodd; Diana M Cardona; Nerissa Williams; Yan Ma; Christoph Lepper; Corinne M Linardic; Sayan Mukherjee; Gerard C Grosveld; Chen-Ming Fan; David G Kirsch

doi:10.1016/j.celrep.2013.10.020

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Distinct and Overlapping Sarcoma Subtypes Initiated from Muscle Stem and Progenitor Cells

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Distinct and Overlapping Sarcoma Subtypes Initiated from Muscle Stem and Progenitor Cells

Rebecca D Dodd, Jordan M Blum, Leonor Añó, Zhizhong Li, David Van Mater, Brian D Bennett, Mohit Sachdeva, Irina Lagutina, Minsi Zhang, Jeffrey K Mito, …

Cell reports (Cambridge), Vol.5(4), pp.933-940

11/27/2013

DOI: 10.1016/j.celrep.2013.10.020

PMCID: PMC3893104

PMID: 24239359

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Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, whereas undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue sarcomas diagnosed in adults. To investigate the myogenic cell(s) of origin of these sarcomas, we used Pax7-CreER and MyoD-CreER mice to transform Pax7+ and MyoD+ myogenic progenitors by expressing oncogenic KrasG12D and deleting Trp53 in vivo. Pax7-CreER mice developed RMS and UPS, whereas MyoD-CreER mice developed UPS. Using gene set enrichment analysis, RMS and UPS each clustered specifically within their human counterparts. These results suggest that RMS and UPS have distinct and overlapping cells of origin within the muscle lineage. Taking them together, we have established mouse models of soft tissue sarcoma from muscle stem and progenitor cells. [Display omitted] •Mouse RMS (mRMS) can be initiated in Pax7+MyoD− muscle stem cells•Mouse UPS (mUPS) can be initiated in Pax7+MyoD+ myogenic progenitors•mUPS cluster separately from mRMS by PCA and hierarchical clustering•mUPS and mRMS enrich in their human counterparts by GSEA Cancer subtype can be influenced by cell of origin. Here, Kirsch and colleagues investigate the impact of cell of origin on sarcoma subtype by initiating mutations in muscle stem and progenitor cells. Tumor initiation in Pax7-expressing cells gave rise to rhabdomyosarcoma and undifferentiated pleomorphic sarcoma, whereas tumor initiation in MyoD-expressing cells gave rise to undifferentiated pleomorphic sarcoma. These results suggest that rhabdomyosarcoma can be initiated in muscle stem cells, whereas undifferentiated pleomorphic sarcoma can be initiated in activated satellite cells and myoblasts.

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Title: Subtitle: Distinct and Overlapping Sarcoma Subtypes Initiated from Muscle Stem and Progenitor Cells
Creators: Rebecca D Dodd - Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
Jordan M Blum - Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Leonor Añó - Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Zhizhong Li - Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
David Van Mater - Department of Pediatrics, Division of Hematology-Oncology, Duke University Medical Center, Durham, NC 27710, USA
Brian D Bennett - Institute for Genome Sciences & Policy, Duke University Medical Center, Durham, NC 27710, USA
Mohit Sachdeva - Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
Irina Lagutina - Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Minsi Zhang - Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Jeffrey K Mito - Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Leslie G Dodd - Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Diana M Cardona - Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
Nerissa Williams - Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
Yan Ma - Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
Christoph Lepper - Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218, USA
Corinne M Linardic - Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Sayan Mukherjee - Computational Biology and Bioinformatics Program, Duke University, Durham, NC 27710, USA
Gerard C Grosveld - Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Chen-Ming Fan - Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218, USA
David G Kirsch - Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.5(4), pp.933-940
Publisher: Elsevier Inc
DOI: 10.1016/j.celrep.2013.10.020
PMID: 24239359
PMCID: PMC3893104
ISSN: 2211-1247
eISSN: 2211-1247
Language: English
Date published: 11/27/2013
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094479102771

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