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PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors [Cut&Run]

ABSTRACT: Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241644 | GEO | 2023/09/30

REPOSITORIES: GEO

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PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors [RNA-seq]

Project description:Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

2023-09-30 | GSE241645 | GEO

PAX3-FOXO1 expression in endothelial progenitors dictates myogenic reprogramming and rhabdomyosarcoma identity[Cut&Run]

Project description:Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a novel FP-RMS mouse model driven by P3F expression and CDKN2A loss in endothelial cells. Additionally, we show that P3F expression in p53 null human iPSCs blocks endothelial directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

2023-09-30 | GSE218265 | GEO

PAX3-FOXO1 expression in endothelial progenitors dictates myogenic reprogramming and rhabdomyosarcoma identity[Hi-C]

Project description:Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a novel FP-RMS mouse model driven by P3F expression and CDKN2A loss in endothelial cells. Additionally, we show that P3F expression in p53 null human iPSCs blocks endothelial directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

2023-09-30 | GSE218254 | GEO

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

Project description: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.

2024-03-05 | GSE260915 | GEO

The BAF complex blocks Myogenesis in rhabdomyosarcoma

Project description:Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer of skeletal muscle lineage. The aggressive alveolar subtype is commonly characterized by t(2;13) or t(1;13) translocations with the expression of PAX3- or PAX7-FOXO1 fusion transcription factors respectively and is known as fusion positive RMS (FP-RMS). FP-RMS tumors rely on the fusion gene to maintain their proliferative state while avoiding terminal differentiation program. Since disruptions of normal development are likely governed by epigenetic changes in these low-mutational-burden tumors, we investigated the contributions of chromatin regulatory complexes to RMS tumor maintenance. We demonstrate the essentiality of the mSWI/SNF ATPase BRG1 for FP-RMS proliferation and discover that RMS significantly overexpress SMARCA4 (encoding BRG1) compared to skeletal muscle. We define the mSWI/SNF subunit repertoire in FP-RMS and provide evidence for the assembly of multiple mSWI/SNF complexes including canonical BAF, PBAF and non-canonical (nc)BAF in FP-RMS. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which was further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with FP-RMS core regulatory transcription factors. We report that mSWI/SNF complexes act as sensors of chromatin state, which are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes. Finally, BRG1 targeting compounds reproduce the effects of genetic ablation. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for treating this lethal childhood tumor.

2021-04-01 | GSE162052 | GEO

Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma [CUT&Run]

Project description:Rhabdomyosarcoma (RMS), a malignancy of impaired myogenic differentiation, is the most common soft tissue pediatric cancer. PAX3-FOXO1 oncofusions drive the majority of the clinically more aggressive fusion-positive rhabdomyosarcoma (FP-RMS). Recent studies have established an epigenetic basis for PAX3-FOXO1-driven oncogenic processes. However, details of PAX3-FOXO1 epigenetic mechanisms, including interactions with, and dependence on, other chromatin and transcription factors, are incompletely understood. We previously identified a novel disease-promoting epigenetic axis in RMS, involving the histone demethylase KDM3A and the ETS1 transcription factor, and demonstrated that this epigenetic axis interfaces with PAX3-FOXO1 both phenotypically and transcriptomically, including co-regulation of biological processes and genes important to FP-RMS progression. In this study, we demonstrate that KDM3A and ETS1 colocalize with PAX3-FOXO1 to enhancers of important disease-promoting genes in FP-RMS, including FGF8, IL4R, and MEST, as well as PODXL, which we define herein as a new FP-RMS-promoting gene. We show that ETS1, which is induced by both PAX3-FOXO1 and KDM3A, exists in complex with PAX3-FOXO1, and augments PAX3-FOXO1 chromatin occupancy. We further show that the PAX3-FOXO1/ETS1 complex can be disrupted by the clinically relevant small molecule inhibitor YK-4-279. YK-4-279 displaces PAX3-FOXO1 from chromatin and interferes with PAX3-FOXO1-dependent gene regulation, resulting in potent inhibition of growth and invasive properties in FP-RMS, along with downregulation of FGF8, IL4R, MEST and PODXL expression. We additionally show that, in some FP-RMS, KDM3A also increases PAX3-FOXO1 levels. Together, our studies illuminate mechanisms of action of the KDM3A/ETS1 regulatory module, and reveal novel targetable mechanisms of PAX3-FOXO1 chromatin complex regulation, in FP-RMS.

2024-10-25 | GSE279336 | GEO

Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma [RNA-Seq]

2024-10-25 | GSE279335 | GEO

The BAF complex blocks Myogenesis in rhabdomyosarcoma

2020-11-20 | MSV000086494 | MassIVE

Culturing human fusion-positive rhabdomyosarcoma cell lines as rhabdospheres enriches for stemness and Notch signaling

Project description:The development of three-dimensional cell culture techniques has allowed cancer researchers to study the stemness properties of cancer cells in in vitro culture. However, a method to grow PAX3-FOXO1-positive fusion-positive rhabdomyosarcoma (FP-RMS) - an aggressive soft tissue sarcoma of childhood - has thus far not been achieved, hampering efforts to identify the dysregulated signaling pathways that underlie FP-RMS stemness. Here, we first examine the expression of canonical stem cell markers in human RMS tumors and cell lines. We then describe a method to grow FP-RMS cell lines as rhabdospheres and demonstrate that these spheres are enriched in expression of canonical stemness factors as well as Notch signaling components. Specifically, FP-RMS rhabdospheres have increased expression of SOX2, POU5F1 (OCT4), and NANOG, and several receptors and transcriptional regulators in the Notch signaling pathway. FP-RMS rhabdospheres also exhibit functional stemness characteristics including multipotency, increased tumorigenicity in vivo, and chemoresistance. This method provides a novel practical tool to support research into FP-RMS stemness and chemoresistance signaling mechanisms. We used microarray to understand the transcriptome profile of rhabdomyosarcoma in different culture condition (adherent, sphere, and xenograft).

2021-02-22 | GSE119716 | GEO

Endothelial and Alveolar Rhabdomyosarcoma mRNA expression

Project description:Frozen skeletal muscle, tumor adjacent skeletal muscle, Endothelial Rhabdomyosarcoma (ERMS) and Alveolar Rhabdomyosarcoma (ARMS) samples were profiled on Illumina bead array. Total RNA from primary resected samples were profiled to allow comparison of 1) normal skeletal muscle tissue with RMS samples and 2) ARMS with ERMS tumors.

2013-12-31 | E-GEOD-28511 | biostudies-arrayexpress

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