Non-coding RNA in rhabdomyosarcoma progression and metastasis

Ramadan, Farah; Saab, Raya; Hussein, Nader; Clézardin, Philippe; Cohen, Pascale A.; Ghayad, Sandra E.

doi:10.3389/fonc.2022.971174

Cited by 7 publications

(11 citation statements)

References 176 publications

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“…E.g., a RAB3IP-HMGA2 fusion transcript is suspected to be a novel driver in a case of adult RMS [ 41 , 42 ]. Non-coding RNA is associated with the initiation, as well as progression, of RMS [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Loss of Chemerin in Rhabdomyosarcoma Cells Polarizes Adjacent Monocytes to an Immunosuppressive Phenotype

et al. 2022

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Chemerin is a multifunctional adipokine that regulates adipogenesis, insulin signaling and blood pressure and has thus a central function in metabolism. Mounting evidence confirmed a function of chemerin in various cancers. In this study, we investigated the role of chemerin in rhabdomyosarcoma (RMS), an aggressive soft tissue cancer that affects mainly children and young adults. We found chemerin expression in 93.8% (90 of 96) of RMS cases, with a range of 86.7–96.7% for the four RMS subgroups. While chemerin is uniformly expressed in normal skeletal muscle, its expression in RMS is patchy with interspersed areas that are devoid of chemerin. This variable chemerin expression is reflected by RMS cell lines as two of them (Rh41 and Rd18) were found to secrete chemerin while the two other ones (JR1 and RD) were negative. Deletion of chemerin in Rh41 and Rd18 cells did not alter their growth rate or morphology. We investigated the potential influence of chemerin on immune surveillance by coculturing parental and chemerin-deficient RMS cells with resting- or lipopolysaccharide (LPS)-activated human peripheral monocytes. The absence of chemerin in the RMS cells led to increased expression levels of the coinhibitory molecules PD-L1 and PD-L2 while levels of the costimulatory molecule CD86 were not changed. Further, the absence of chemerin enhanced the secretion of cytokines (IL-1β, IL-6, IL-10 and TNF) that have been shown to support RMS pathogenesis. These data indicate that the loss of chemerin expression by RMS cells repolarizes monocytes in the tumor microenvironment to supporting tumor progression.

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Section: Discussionmentioning

confidence: 99%

Loss of Chemerin in Rhabdomyosarcoma Cells Polarizes Adjacent Monocytes to an Immunosuppressive Phenotype

et al. 2022

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“…MiRNAs are short ncRNAs of about 22 nucleotides, which are produced in the nucleus as pri-miRNAs and then processed by the Drosha complex into shorter precursors of about 70 nucleotides called pre-miRNAs. Pre-miRNAs translocate to the cytoplasm, where they are processed again by the DICER1 enzyme to give rise to mature miRNAs [149,150]. MiRNAs function by binding to complementary sequences on target mRNAs, resulting in translational repression or mRNA degradation, depending on the grade of complementarity between the seed region of the miRNA and the 3 untranslated region (UTR) of the target mRNA [151].…”

Section: Microrna (Mirna)-dependent Post-transcriptional Dysregulatio...mentioning

confidence: 99%

“…Consequently, they share the same mRNA targets. MiR-206 is the only miRNA exclusively expressed in skeletal muscle [150]. MyomiR targets include Histone deacetylase 4 (HDAC4) [157] and the SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily D, Member 1 (SMARCD1/BAF60a) subunit of the mSWI/SNF chromatin remodeling complex [158].…”

Section: Myomir Family Of Mirnasmentioning

confidence: 99%

Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Pomella

Danielli

Alaggio

et al. 2023

Cancers

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Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention.

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“…The super clusters assembled at myogenic TFs such as MYOD1 maintain expression and a myoblast-like state, and PAX3-FOXO1 is locked by an infinite loop of myogenic enhancer logic via the myogenic TF-responsive super enhancer on the FOXO1 side of the translocation [ 10 ]. Derailed myogenic cell fate in RMS also corresponds with aberrant expression of myogenic ncRNAs [ 11 ], and PAX3-FOXO1 specifically drives miRNAs that contribute to disease pathogenesis [ 12 ]. The transcriptional repression of correct myogenic programs is also coordinated by epigenetic machinery, such as the NCOR/HDAC3 complex [ 13 ], the CHD4/NuRD complex [ 14 ], and the BAF complex [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

BET Bromodomain Degradation Disrupts Function but Not 3D Formation of RNA Pol2 Clusters

et al. 2023

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Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by a translocation that creates the chimeric transcription factor PAX3-FOXO1 (P3F), which assembles de novo super enhancers to drive high levels of transcription of other core regulatory transcription factors (CRTFs). P3F recruits co-regulatory factors to super enhancers such as BRD4, which recognizes acetylated lysines via BET bromodomains. In this study, we demonstrate that inhibition or degradation of BRD4 leads to global decreases in transcription, and selective downregulation of CRTFs. We also show that the BRD4 degrader ARV-771 halts transcription while preserving RNA Polymerase II (Pol2) loops between super enhancers and their target genes, and causes the removal of Pol2 only past the transcriptional end site of CRTF genes, suggesting a novel effect of BRD4 on Pol2 looping. We finally test the most potent molecule, inhibitor BMS-986158, in an orthotopic PDX mouse model of FP-RMS with additional high-risk mutations, and find that it is well tolerated in vivo and leads to an average decrease in tumor size. This effort represents a partnership with an FP-RMS patient and family advocates to make preclinical data rapidly accessible to the family, and to generate data to inform future patients who develop this disease.

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Non-coding RNA in rhabdomyosarcoma progression and metastasis

Cited by 7 publications

References 176 publications

Loss of Chemerin in Rhabdomyosarcoma Cells Polarizes Adjacent Monocytes to an Immunosuppressive Phenotype

Loss of Chemerin in Rhabdomyosarcoma Cells Polarizes Adjacent Monocytes to an Immunosuppressive Phenotype

Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

BET Bromodomain Degradation Disrupts Function but Not 3D Formation of RNA Pol2 Clusters

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