RAS signaling dysregulation in human embryonal Rhabdomyosarcoma

Martinelli, Simone; McDowell, Heather P.; Vigne, Silvia Delle; Kokai, George; Uccini, Stefania; Tartaglia, Marco; Dominici, Carlo

doi:10.1002/gcc.20702

Cited by 90 publications

(92 citation statements)

References 43 publications

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“…Consistent with a central role of Ras signaling in these tumors, inhibition of Ras/Raf/MEK/ERK signaling reduced the proliferation of mouse and human sarcoma cells (20). Thus, although the present study does not specifically interrogate the relative importance of Ras pathway activation compared with other possible sarcoma-relevant oncogenic events (2), our findings highlight the important contribution of aberrant Ras signaling to the growth and malignancy of STS (6,11,12,20).…”

Section: Discussionsupporting

confidence: 76%

“…Thus, activated Ras/Raf/MEK/ERK signaling contributes to sarcoma growth, consistent with its prominence in our bioinformatic analyses (Fig. 3 and Table S3) (6,(11)(12)(13)20).…”

Section: Distinct Myogenic Marker Expression Insupporting

confidence: 82%

“…A number of oncogenetic lesions have been linked to these tumors. Activating Ras mutations can be found in up to 35% of human embryonal RMS (11,12), and in up to 44% of human STS (13). Ectopic expression of oncogenic Kras induces RMS in zebrafish (6) and cooperates with loss of tumor protein p53 (Tp53) to induce RMS when activated broadly in whole mouse muscle (14).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 76%

“…Thus, activated Ras/Raf/MEK/ERK signaling contributes to sarcoma growth, consistent with its prominence in our bioinformatic analyses (Fig. 3 and Table S3) (6,(11)(12)(13)20).…”

Section: Distinct Myogenic Marker Expression Insupporting

confidence: 82%

mentioning

confidence: 99%

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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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“…By contrast, ERMS is often associated with loss of heterozygosity at chromosome 11p15 and a number of whole chromosomal gains (Wexler and Helman, 1994;Barr, 1997;Arndt and Crist, 1999). Activating mutations in RAS family members have been described in a minority of ERMS cases (Stratton et al, 1989;Chen et al, 2006;Martinelli et al, 2009), and gene expression analysis on a number of tumors suggests that RAS pathway activation might be a common event in ERMS formation, even in the absence of RAS mutations .…”

Section: Introductionmentioning

confidence: 99%

Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis

et al. 2013

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SUMMARYRhabdomyosarcoma is a pediatric malignancy thought to arise from the uncontrolled proliferation of myogenic cells. Here, we have generated models of rhabdomyosarcoma in the zebrafish by inducing oncogenic KRAS G12D expression at different stages during muscle development. Several zebrafish promoters were used, including the cdh15 and rag2 promoters, which drive gene expression in early muscle progenitors, and the mylz2 promoter, which is expressed in differentiating myoblasts. profound effects on the ability of tumor cells to recapitulate normal myogenesis, altering the tumorigenic capability of these cells.

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“…RAS Mutations [12,13] SHH Activation [14] IGF2 Loss of imprinting [15,16] EGFR Overexpression [17,18] translocation-positive RMS PAX/FKHR Translocation [11,19] NMYC Amplification [20] FGFR4 Mutations [21,22] CB1 - [23] IL4R…”

Section: Translocation-negative Rmsmentioning

confidence: 99%

Multidisciplinary management of childhood sarcoma: time to expand

Schäfer

Niggli

2010

Expert Review of Anticancer Therapy

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"…our knowledge regarding different entities in sarcoma has considerably increased over the last two decades, and this information among others has helped to classify sarcomas more precisely and to identify new subgroups."Sarcomas are a heterogeneous group of tumors. In the last 20 years, the finding of specific acquired chromosomal alterations in sarcomas has helped, in many cases, to understand their underlying genetic basis. Each of the various recurrent chromosomal translocations in sarcomas ultimately results in the creation of a novel chimeric or fusion gene. With the discovery of these new chromosomal alterations in sarcomas, and subsequently of the fusion genes, it was believed that remarkable progress would be possible in the treatment approach for these tumors. Certainly, our knowledge regarding different entities in sarcoma has considerably increased over the last two decades, and this information among others has helped to classify sarcomas more precisely and to identify new subgroups. However, whether this information has also translated into a better treatment approach is questionable. In children, rhabdomyosarcoma (RMS) is the most common malignant soft-tissue tumor. Although combined treatment modalities including surgery, chemotherapy and/or radiotherapy have increased overall survival in many RMSs and other groups of soft-tissue sarcomas, conventional treatment has not yet resolved the problem of metastatic disease and many situations of disease relapse.Furthermore, another important concern is the side effects of conventional chemotherapy and especially radio therapy. Since most current therapies are not specifically targeted to tumor cells, a variety of normal cells in the body may also be affected by these therapeutic modalities, resulting in undesired and long-term side effects in the developing child."Although combined treatment modalities … have increased overall survival in many rhabdomyosarcomas and other groups of soft-tissue sarcomas, conventional treatment has not yet resolved the problem of metastatic disease and many situations of disease relapse."Optimization of chemotherapy has certainly brought some improvement but it is unlikely to deliver a real breakthrough in the therapeutic approach. Combination therapies including vincristine, dactinomycin and cyclophosphamide or ifosfamide can be considered as the backbone of current treatment protocols. Other antineoplastic agents including doxorubicin, cisplatin, carboplatin, etoposide, topotecan, irinotecan, melphalan and methotrexate are active against RMS and have been combined in various combinations with backbone drugs. The overall survival rate in non-metastatic RMS has reached approximately 70%. However, substantial differences can be observed according to tumor site and clinical stage, ranging from approximately 60%, for example, in RMS of the limbs, to 90% or higher in orbital RMS or in genitourinary and nonbladder

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RAS signaling dysregulation in human embryonal Rhabdomyosarcoma

Cited by 90 publications

References 43 publications

Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells

Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells

Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis

Multidisciplinary management of childhood sarcoma: time to expand

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