Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

Kashi, Venkatesh P.; Hatley, Mark E.; Galindo, Rene L.

doi:10.1038/nrc3961

Cited by 113 publications

(131 citation statements)

References 146 publications

(145 reference statements)

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“…Unfortunately, RMS patients that survive current cytotoxic drug therapies have an increased risk for several diseases later in life (3), emphasizing the critical need for development of new mechanism-based therapies which have fewer long term adverse effects. Results of PAX3-FOXO1A knockdown or overexpression studies in RMS and other cell lines demonstrate the functional importance of this fusion gene in maintaining the aggressive cancer cell phenotype and this is due, in part, to the pro-oncogenic PAX3-FOX01-regulated genes (39,42). Development of agents that target PAX3-FOXO1A is ongoing and includes thapsigargin, fenretinide, HDAC inhibitors, and polo-like kinase inhibitors; however, the efficacy of these compounds for clinical applications in ARMS chemotherapy is not known (43–47).…”

Section: Discussionmentioning

confidence: 98%

“…RMS is primarily observed in children and adolescents and accounts for 5% of all pediatric cancers and 50% of soft tissue sarcomas in children (39). Although ERMS patients respond well to current therapies which include surgery and radiotherapy combined with treatment with cytotoxic drug combinations, patients with ARMS have a poor diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…Cytogenetic analysis has demonstrated that 2;13 and 1;13 chromosomal translocations generating PAX3-FOXO1A and PAX7-FOXO1A fusion genes, respectively, are highly prevalent (55% and 22%, respectively) in tumors from ARMS patients. The PAX3-FOXO1A fusion gene is the critical prognostic marker for ARMS patients with metastatic disease, with an estimated overall 4 year survival of 8% compared to 75% survival rate of patients with PAX7-FOXO1A-expressing tumors (39–41). Unfortunately, RMS patients that survive current cytotoxic drug therapies have an increased risk for several diseases later in life (3), emphasizing the critical need for development of new mechanism-based therapies which have fewer long term adverse effects.…”

Section: Discussionmentioning

confidence: 99%

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PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

2017

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Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric disease driven by expression of the oncogenic fusion gene PAX3-FOXO1A. In this study, we report overexpression of the nuclear receptor NR4A1 is rhabdomyosarcomas which is sufficient to drive high expression of PAX3-FOXO1A there. RNAi-mediated silencing of NR4A1 decreased expression of PAX3-FOXO1A and its downstream effector genes. Similarly, cell treatment with the NR4A1 small molecule antagonists 1,1-bis(3-indolyl)-1-(p-hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A. Mechanistic investigations revealed a requirement for the NR4A1/Sp4 complex to bind GC-rich promoter regions to elevate transcription of the PAX3-FOXO1A gene. In parallel, NR4A1 also regulated expression of β1-integrin which with PAX3-FOXO1A contributed to tumor cell migration that was blocked by C-DIM/NR4A1 antagonists. Taken together, our results provide a preclinical rationale for the use of NR4A1 small molecule antagonists to treat ARMS and other rhabdomyosarcomas driven by PAX3-FOXO1A.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

2017

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“…The model has also been used to identify functional heterogeneity in molecularly defined cell types, including isolation of myf5:GFP+ TPCs (Ignatius et al, 2012). In total, the zebrafish kRAS G12D ERMS model has emerged as one of the most relevant for discovering pathways that drive cancer growth in human RMS (Chen et al, 2013a, 2014; Ignatius et al, 2012; Kashi et al, 2015; Langenau et al, 2007, 2008; Le et al, 2013; Storer et al, 2013; Tang et al, 2016)…”

Section: Introductionmentioning

confidence: 99%

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Tenente

Hayes

Ignatius

et al. 2017

eLife

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Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth.DOI: http://dx.doi.org/10.7554/eLife.19214.001

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“…7, 8 Despite the expression of Mrfs, RMS cells arrest and fail to properly execute terminal muscle differentiation. 9 FN-RMS cells also maintain high expression of PAX7 and PAX3, transcription factors that promote proliferation and self-renewal in myogenic satellite cells. 10, 11 However, the full constellation of factors contributing to the differentiation arrest in RMS remains elusive.…”

mentioning

confidence: 99%

PAX7 is a required target for microRNA-206-induced differentiation of fusion-negative rhabdomyosarcoma

Hanna

Garcia

et al. 2016

Cell Death Dis

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. RMS can be parsed based on clinical outcome into two subtypes, fusion-positive RMS (FP-RMS) or fusion-negative RMS (FN-RMS) based on the presence or absence of either PAX3-FOXO1 or PAX7-FOXO1 gene fusions. In both RMS subtypes, tumor cells show histology and a gene expression pattern resembling that of developmentally arrested skeletal muscle. Differentiation therapy is an attractive approach to embryonal tumors of childhood including RMS; however, agents to drive RMS differentiation have not entered the clinic and their mechanisms remain unclear. MicroRNA-206 (miR-206) expression increases through normal muscle development and has decreased levels in RMS compared with normal skeletal muscle. Increasing miR-206 expression drives differentiation of RMS, but the target genes responsible for the relief of the development arrest are largely unknown. Using a combinatorial approach with gene and proteomic profiling coupled with genetic rescue, we identified key miR-206 targets responsible for the FN-RMS differentiation blockade, PAX7, PAX3, NOTCH3, and CCND2. Specifically, we determined that PAX7 downregulation is necessary for miR-206-induced cell cycle exit and myogenic differentiation in FN-RMS but not in FP-RMS. Gene knockdown of targets necessary for miR-206-induced differentiation alone or in combination was not sufficient to phenocopy the differentiation phenotype from miR-206, thus illustrating that miR-206 replacement offers the ability to modulate a complex network of genes responsible for the developmental arrest in FN-RMS. Genetic deletion of miR-206 in a mouse model of FN-RMS accelerated and exacerbated tumor development, indicating that both in vitro and in vivo miR-206 acts as a tumor suppressor in FN-RMS at least partially through downregulation of PAX7. Collectively, our results illustrate that miR-206 relieves the differentiation arrest in FN-RMS and suggests that miR-206 replacement could be a potential therapeutic differentiation strategy.

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Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

Cited by 113 publications

References 146 publications

PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

PAX7 is a required target for microRNA-206-induced differentiation of fusion-negative rhabdomyosarcoma

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