Advances in sarcoma genomics and new therapeutic targets

Taylor, Barry S.; Barretina, Jordi; Maki, Robert G.; Antonescu, Cristina R.; Singer, Samuel; Ladanyi, Marc

doi:10.1038/nrc3087

Cited by 368 publications

(359 citation statements)

References 199 publications

(217 reference statements)

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“…sarcoma | FOXM1 | YAP | Hippo S oft-tissue sarcomas (STS) are heterogeneous mesenchymal tumors diagnosed annually in >200,000 people worldwide (1). STS comprise multiple histologically distinct tumor types, with fibrosarcoma, liposarcoma, and undifferentiated pleomorphic sarcoma (UPS) among the most commonly detected in adults.…”

mentioning

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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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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mentioning

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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“…57 The significant diversity of soft tissue neoplasms associated with EWSR1 gene rearrangements is well known 58 ; EWSR1 is capable of fusing with several different partner genes, which can sometimes result in the formation of histologically identical neoplasms but can also fuse with the same genes to generate morphologically and behaviorally different tumors. It is not fully understood how identical gene fusions can generate such different tumor types, although a possible explanation might be that these neoplasms originate from specific progenitor cells in different anatomic sites, 59 with the differing phenotypes corresponding to the particular cell of origin. Overall, gene expression patterns are likely to vary considerably between tumor types, contributing to their significant clinicopathological differences.…”

Section: Histopathologymentioning

confidence: 99%

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

Thway

Fisher

2015

Archives of Pathology &Amp; Laboratory Medicine

107

134

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Context.-Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the superficial extremities of children and young adults. While it has characteristic histologic features of nodular distributions of ovoid and spindle cells with blood-filled cystic cavities and a surrounding dense lymphoplasmacytic infiltrate, there is a significant morphologic spectrum, which coupled with its rarity and lack of specific immunoprofile can make diagnosis challenging. Angiomatoid fibrous histiocytoma is associated with 3 characteristic gene fusions, EWSR1-CREB1 and EWSR1-ATF1, which are also described in other neoplasms, and rarely FUS-ATF1. Angiomatoid fibrous histiocytoma is now recognized at an increasing number of sites and is known to display a variety of unusual histologic features.Objective.-To review the current status of AFH, discussing putative etiology, histopathology with variant morphology and differential diagnosis, and current genetics, including overlap with other tumors harboring EWSR1-CREB1 and EWSR1-ATF1 fusions.Data Sources.-Review of published literature, including case series, case reports, and review articles, in online medical databases.Conclusions.-The occurrence of AFH at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its small risk of metastasis and death. This highlights the importance of diagnostic recognition, ancillary molecular genetic confirmation, and close clinical follow-up of patients with AFH. Further insight into the genetic and epigenetic changes arising secondary to the characteristic gene fusions of AFH will be integral to understanding its tumorigenic mechanisms.

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“…Furthermore, genome aberrations revealed by gene expression arrays are not always correlated to tumor behavior characteristics in the individual patient [5][6][7] . In order to try and solve these problems, personalized medicine has gained in importance, which is reflected in the increased search for xenograft models [8][9][10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

The <em>In ovo</em> CAM-assay as a Xenograft Model for Sarcoma

Sys

Lapeire

Stevens

et al. 2013

JoVE

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Citation: Sys, G.M.L., Lapeire, L., Stevens, N., Favoreel, H., Forsyth, R., Bracke, M., De Wever, O. The In ovo CAM-assay as a Xenograft Model for Sarcoma. J. Vis. Exp. (77), e50522, doi:10.3791/50522 (2013). AbstractSarcoma is a very rare disease that is heterogeneous in nature, all hampering the development of new therapies. Sarcoma patients are ideal candidates for personalized medicine after stratification, explaining the current interest in developing a reproducible and low-cost xenotransplant model for this disease. The chick chorioallantoic membrane is a natural immunodeficient host capable of sustaining grafted tissues and cells without species-specific restrictions. In addition, it is easily accessed, manipulated and imaged using optical and fluorescence stereomicroscopy. Histology further allows detailed analysis of heterotypic cellular interactions.This protocol describes in detail the in ovo grafting of the chorioallantoic membrane with fresh sarcoma-derived tumor tissues, their single cell suspensions, and permanent and transient fluorescently labeled established sarcoma cell lines (Saos-2 and SW1353). The chick survival rates are up to 75%. The model is used to study graft-(viability, Ki67 proliferation index, necrosis, infiltration) and host (fibroblast infiltration, vascular ingrowth) behavior. For localized grafting of single cell suspensions, ECM gel provides significant advantages over inert containment materials. The Ki67 proliferation index is related to the distance of the cells from the surface of the CAM and the duration of application on the CAM, the latter determining a time frame for the addition of therapeutic products. Video LinkThe video component of this article can be found at

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Advances in sarcoma genomics and new therapeutic targets

Cited by 368 publications

References 199 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

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

The <em>In ovo</em> CAM-assay as a Xenograft Model for Sarcoma

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