Cross Species Genomic Analysis Identifies a Mouse Model as Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma

Mito, Jeffrey K.; Riedel, Richard F.; Dodd, Leslie G.; Lahat, Guy; Lazar, Alexander J.; Dodd, Rebecca D.; Stangenberg, Lars; Eward, William C.; Hornicek, Francis J.; Yoon, Sam S.; Brigman, Brian E.; Jacks, Tyler; Lev, Dina; Mukherjee, Sayan; Kirsch, David G.

doi:10.1371/journal.pone.0008075

Cited by 71 publications

(89 citation statements)

References 16 publications

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“…Murine sarcoma cells were derived from the autochthonous KP and KIA models of UPS. Tumors that develop in these mice, after Adeno-Cre virus injection into the left gastrocnemius muscle, recapitulate human UPS morphologically and histologically while harboring similar gene-expression profiles (4,22,25). Additionally, hindlimb tumors successfully metastasize to the lung, mirroring human UPS.…”

Section: Yap Inhibition Results In Decreased Sarcoma Cell Proliferatimentioning

confidence: 83%

“…Further analysis of metastatic lesions is required to determine whether metastatic cells also rely on YAP/TEAD/FOXM1. Of note, YAP and FOXM1 clearly play a role in cell migration/invasion and metastasis in other contexts (41,42), and, importantly, FOXM1 has been associated specifically with UPS metastasis (25). It will be interesting to determine whether YAP and FOXM1 coregulate metastatic progression beyond their control of proliferation in the primary tumor.…”

Section: Discussionmentioning

confidence: 99%

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Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Eisinger-Mathason

Mucaj

Biju

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.

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Section: Yap Inhibition Results In Decreased Sarcoma Cell Proliferatimentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Eisinger-Mathason

Mucaj

Biju

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…These data indicate that the core transcriptional profile of Kras; p16p19 null mouse sarcomas is remarkably similar. For this reason, our subsequent bioinformatic analyses (described below) considered all 12 sarcoma samples together in comparison with normal mouse skeletal muscle (the anatomic site from which the tumor cells-of-origin were isolated and where tumors emerged (Dataset S1) (29)(30)(31)(32).…”

Section: Distinct Myogenic Marker Expression Inmentioning

confidence: 99%

Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells

Hettmer

Liu

Miller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Soft-tissue sarcomas are heterogeneous cancers that can present with tissue-specific differentiation markers. To examine the cellular basis for this histopathological variation and to identify sarcoma-relevant molecular pathways, we generated a chimeric mouse model in which sarcoma-associated genetic lesions can be introduced into discrete, muscle-resident myogenic and mesenchymal cell lineages. Expression of Kirsten rat sarcoma viral oncogene [ Kras ( G12V )] and disruption of cyclin-dependent kinase inhibitor 2A ( CDKN2A ; p16p19 ) in prospectively isolated satellite cells gave rise to pleomorphic rhabdomyosarcomas (MyoD-, Myogenin- and Desmin-positive), whereas introduction of the same oncogenetic hits in nonmyogenic progenitors induced pleomorphic sarcomas lacking myogenic features. Transcriptional profiling demonstrated that myogenic and nonmyogenic Kras; p16p19 null sarcomas recapitulate gene-expression signatures of human rhabdomyosarcomas and identified a cluster of genes that is concordantly up-regulated in both mouse and human sarcomas. This cluster includes genes associated with Ras and mechanistic target of rapamycin (mTOR) signaling, a finding consistent with activation of the Ras and mTOR pathways both in Kras; p16p19 null sarcomas and in 26–50% of human rhabdomyosarcomas surveyed. Moreover, chemical inhibition of Ras or mTOR signaling arrested the growth of mouse Kras; p16p19 null sarcomas and of human rhabdomyosarcoma cells in vitro and in vivo. Taken together, these data demonstrate the critical importance of lineage commitment within the tumor cell-of-origin in determining sarcoma histotype and introduce an experimental platform for rapid dissection of sarcoma-relevant cellular and molecular events.

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“…Genetically, UPS sarcomas display a complex karyotype reflecting genomic instability. There are no known single oncogenic mutations associated with UPS, although activation of the Kras pathway might be involved (Mito et al, 2009). Because the cell of origin for this tumor remains unclear, some have suggested that UPS is not a distinct clinical entity, but instead represents a common undifferentiated state of diverse tumors that are derived from different mesenchymal cells.…”

Section: Undifferentiated Pleomorphic Sarcomamentioning

confidence: 99%

Animal models of soft-tissue sarcoma

Dodd

Mito

Kirsch

2010

Disease Models &Amp; Mechanisms

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Soft-tissue sarcomas (STSs) are rare mesenchymal tumors that arise from muscle, fat and connective tissue. Currently, over 75 subtypes of STS are recognized. The rarity and heterogeneity of patient samples complicate clinical investigations into sarcoma biology. Model organisms might provide traction to our understanding and treatment of the disease. Over the past 10 years, many successful animal models of STS have been developed, primarily genetically engineered mice and zebrafish. These models are useful for studying the relevant oncogenes, signaling pathways and other cell changes involved in generating STSs. Recently, these model systems have become preclinical platforms in which to evaluate new drugs and treatment regimens. Thus, animal models are useful surrogates for understanding STS disease susceptibility and pathogenesis as well as for testing potential therapeutic strategies.

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Cross Species Genomic Analysis Identifies a Mouse Model as Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma

Cited by 71 publications

References 16 publications

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells

Animal models of soft-tissue sarcoma

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