Evidence for an Unanticipated Relationship between Undifferentiated Pleomorphic Sarcoma and Embryonal Rhabdomyosarcoma

Rubin, Brian P.; Nishijo, Koichi; Chen, Hung I Harry; Yi, Xiaolan; Schuetze, David; Pal, Ranadip; Prajapati, Suresh I.; Abraham, Jinu; Arenkiel, Benjamin R.; Chen, Qing Rong; Davis, Sean; McCleish, Amanda T.; Capecchi, Mario R.; Michalek, Joel E.; Zarzabal, Lee Ann; Khan, Javed; Yu, Zhongxin; Parham, David M.; Barr, Frederic G.; Meltzer, Paul S.; Chen, Yidong; Keller, Charles

doi:10.1016/j.ccr.2010.12.023

Cited by 167 publications

(259 citation statements)

References 58 publications

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“…21,22 Patients who have localized RMS have a 5-year survival greater than 70% following a multimodal approach that includes chemotherapy, radiation therapy, and surgery; yet, overall survival of patients with metastasis remains poor. 23,24 Cells mainly deriving from myogenic lineages have been shown to contribute to RMS development in mouse [25][26][27][28] and zebrafish models, 29 yet even nonmyogenic lineages could participate in the formation of RMS. 30 As a result, these tumors can arise in or near to skeletal muscle districts as well as in sites that lack skeletal muscle, such as the biliary and genitourinary tract.…”

Section: Rhabdomyosarcomamentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

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Section: Rhabdomyosarcomamentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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“…STS vary clinically and histopathologically (1,2), and this heterogeneity may result from differences in the lineage commitment and differentiation state of the sarcoma cell-of-origin, from genetic or epigenetic changes that occur during transformation, or from a combination of these factors (3). Sarcomas with myogenic features constitute the large and varied category of rhabdomyosarcomas (RMS) (4,5), for which satellite cells (6,7), more differentiated muscle-lineage cells (3,8), and undifferentiated mesenchymal cells (9) have been discussed as putative cells-of-origin. Still, the network of cellular and molecular events driving sarcomas in muscle is largely unknown (10).…”

mentioning

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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“…Next we examined the gene expression of the following factors in RD cells upon p53 activation: MRFs 8,9,14 (MyoD and myogenin), muscle stem cell markers 33,34 (Pax3, Pax7, and cMet), and cancer stem cell-like markers 35 (Oct4, Nanog, Sox2, and CD133). We did not observe significant changes in expression of MyoD, Pax genes, and most of the cancer stem cell-like markers ( Figure 1c and Supplementary Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

et al. 2014

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Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging. Cell Death and Differentiation (2015) 22, 560-573; doi:10.1038/cdd.2014; published online 12 December 2014The tumor suppressor p53 promotes cell cycle arrest or apoptosis in response to diverse stress signals such as DNA damage, thus preventing propagation of genetically compromised cells. [1][2][3] Among the diverse functions attributed to p53, a growing body of evidence supports its role in regulation of differentiation and maintenance of cellular function and integrity. 1,[4][5][6][7] For example, p53 represses Nanog to maintain genetic stability of the stem cell pool by promoting differentiation of mouse embryonic stem cells (mESCs) after DNA damage. 6 Skeletal muscle differentiation, a key step during muscle tissue formation, is orchestrated by the MyoD family of myogenic regulatory factors (MRFs). MyoD determines the myogenic lineage, whereas myogenin, a member of the MRF family, functions downstream of MyoD and plays a critical role in driving terminal differentiation as myogenin-null mice show a lethal deficiency of differentiated skeletal muscle. [8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro. [15][16][17][18][19][20] In contrast, under stress-associated conditions such as inflammation, chronic exposure to double-strand DNA breaks, and aging, enhanced p53 activity has been shown to correlate with skeletal muscle atrophy in vivo. [21][22][23][24][25] In addition, it has been shown that p53 and its downstream effectors are required for an inflammatory cytokine-mediated inhibition of myogenic differentiation in vitro. 22 Int...

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Evidence for an Unanticipated Relationship between Undifferentiated Pleomorphic Sarcoma and Embryonal Rhabdomyosarcoma

Cited by 167 publications

References 58 publications

Uncovering metabolism in rhabdomyosarcoma

Uncovering metabolism in rhabdomyosarcoma

Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

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