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Alveolar Soft Part Sarcoma is driven by ASPSCR1::TFE3-dependent and therapeutically targetable transcriptional programs [RNA-Seq]

ABSTRACT: Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion, though the mechanisms by which this oncogenic transcriptional regulator drives cancer growth are poorly understood. Here, we characterize the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential role of ASPSCR1::TFE3 in tumor cell viability by regulating core transcriptional programs including cell proliferation, angiogenesis, and mitochondrial biology. ASPSCR1::TFE3 directly interacts with key epigenetic regulators at enhancers and promoters to support ASPS-associated transcription. Among the effector programs driven by ASPSCR1::TFE3, cell proliferation was driven by high levels of Cyclin D1 expression, and disruption of Cyclin D1/CDK4 signaling led to loss of ASPS proliferative capacity, which when combined with angiogenesis inhibition halted tumor growth in xenografts. These results define the ASPS oncogenic program, mechanisms by which ASPSCR1::TFE3 controls tumor biology, and identify a strategy for therapeutically targeting tumor cell-intrinsic vulnerabilities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235738 | GEO | 2024/04/19

REPOSITORIES: GEO

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Alveolar Soft Part Sarcoma is driven by ASPSCR1::TFE3-dependent and therapeutically targetable transcriptional programs [ATAC-Seq]

Project description:Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion, though the mechanisms by which this oncogenic transcriptional regulator drives cancer growth are poorly understood. Here, we characterize the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential role of ASPSCR1::TFE3 in tumor cell viability by regulating core transcriptional programs including cell proliferation, angiogenesis, and mitochondrial biology. ASPSCR1::TFE3 directly interacts with key epigenetic regulators at enhancers and promoters to support ASPS-associated transcription. Among the effector programs driven by ASPSCR1::TFE3, cell proliferation was driven by high levels of Cyclin D1 expression, and disruption of Cyclin D1/CDK4 signaling led to loss of ASPS proliferative capacity, which when combined with angiogenesis inhibition halted tumor growth in xenografts. These results define the ASPS oncogenic program, mechanisms by which ASPSCR1::TFE3 controls tumor biology, and identify a strategy for therapeutically targeting tumor cell-intrinsic vulnerabilities.

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Alveolar Soft Part Sarcoma is driven by ASPSCR1::TFE3-dependent and therapeutically targetable transcriptional programs [ChIP-Seq]

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ASPSCR1::TFE3 Drives Alveolar Soft Part Sarcoma by Inducing Targetable Transcriptional Programs

Project description:This SuperSeries is composed of the SubSeries listed below. Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion. A better understanding of the mechanisms by which this oncogenic transcriptional regulator drives cancer growth is needed to help identify potential therapeutic targets. Here, we characterized the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential role of ASPSCR1::TFE3 in tumor cell viability by regulating core transcriptional programs involved in cell proliferation, angiogenesis, and mitochondrial biology. ASPSCR1::TFE3 directly interacted with key epigenetic regulators at enhancers and promoters to support ASPS-associated transcription. Among the effector programs driven by ASPSCR1::TFE3, cell proliferation was driven by high levels of cyclin D1 expression. Disruption of cyclin D1/CDK4 signaling led to loss of ASPS proliferative capacity, and combined inhibition of CDK4/6 and angiogenesis halted tumor growth in xenografts. These results define the ASPS oncogenic program, reveal mechanisms by which ASPSCR1::TFE3 controls tumor biology, and identify a strategy for therapeutically targeting tumor cell-intrinsic vulnerabilities.

2024-04-19 | GSE235739 | GEO

ASPSCR1-TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma 3

Project description:Alveolar soft part sarcoma (ASPS) is a rare soft part malignancy affecting adolescents and young adult. ASPS is characterized by its alveolar structure consisting of tumor cells and highly integrated vascular network, and its high metastatic potential indicates the importance of the prominent angiogenic activity of ASPS. Here we find that the expression of ASPSCR1-TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance but required for in vivo tumor development via angiogenesis. ASPSCR1-TFE3 frequently associates with active enhancers including super-enhancers (SE) upon its DNA binding, and the loss of its expression induces dynamic modification of SE distribution related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identify Pdgfb, Rab27a, Sytl2, and Vwf as critical target genes associated with reduced enhancer activities due to the ASPSCR1-TFE3 loss. ASPSCR1-TFE3 thus orchestrates higher ordered angiogenesis via enhanced intracellular trafficking of angiogenic factors.

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ASPSCR1-TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma [ChIP-seq]

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ASPSCR1-TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma I

2023-01-20 | GSE186789 | GEO

ASPSCR1-TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma 2

2023-01-20 | GSE215264 | GEO

Gene expression profiles of mouse embryonic mesenchymal cells expressing ASPSCR1-TFE3

Project description:Alveolar soft part sarcoma (ASPS) is a slowly growing but highly metastatic sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and abundant vascular network that is responsible for metastatic activities at the initial stage. Here we have generated a new ex vivo mouse model for ASPS that well recapitulates angiogenic and metastatic phenotypes. In mouse ASPS the tumor cells frequently show tumor intravasation, and the intravascular tumor cells were present as organoid structures covered with hemangiopericytes, which is also the case in human ASPS. High expression of GPNMB, a transcriptional target of ASPSCR1-TFE3, was observed at the intravasation. ASPS tumor cells showed the enhanced activity of transendothelial migration and the activity was inhibited by silencing of Gpnmb, indicating that GPNMB plays an important role in tumor intravasation, one of key steps in cancer metastasis. The present model also enabled to evaluate the function of TFE/MITF family transcription factors, and ASPSCR1-TFEB also possessed definitive but less oncogenic activity than that of ASPSCR1-TFE3. Collectively, our new mouse model is a useful tool to understand oncogenic, angiogenic and metastatic mechanisms of ASPS, to identify important motif within the ASPSCR1-TFE3 fusion protein and to provide a novel therapeutic strategy. We used microarrays to detail the global programme of gene expression by introduction of ASPSCR1-TFE3 into mouse embryonic mesenchymal cells.

2017-03-07 | GSE86500 | GEO

Hexameric VCP/p97 reprograms transcription by organizing enhancers with the ASPSCR1-TFE3 fusion oncoprotein

Project description:Aberrant transcription in alveolar soft part sarcoma (ASPS) is orchestrated by the fusion oncoprotein, ASPSCR1-TFE3, resulting from a gene fusion created by a t(X;17) chromosomal translocation. Proteomic analysis of co-immunoprecipitated ASPSCR1-TFE3 complexes revealed strong enrichment of VCP/p97, an AAA+ ATPase with known segregase function. VCP and ASPSCR1-TFE3 co-distributed across chromatin and were associated with active enhancers, indicated by flanking peaks of H3K27ac that assemble into higher order chromatin structures by HiChIP. Positive and negative genetic experiments with ASPSCR1-TFE3 and VCP demonstrated that they function co-dependently for cancer cell proliferation, colony formation, enhancer activation, chromatin conformation, and transcription. The VCP associating with ASPSCR1-TFE3 was found by native gel and electron microscopy to be assembled into homo-hexamers. Disruption of VCP hexamer assembly or enzymatic function inhibited the transcriptional impact of ASPSCR1-TFE3. Thus, a segregase was found to bind chromatin and assemble into 3-dimensional structures as a co-factor of transcriptional regulation.

2023-11-23 | PXD022515 | Pride

ASPSCR1-TFE3 reprograms transcription by organizing enhancers around hexameric VCP [hASPS_ChIP, ASPL_VCP_Pol2]

Project description:Aberrant transcription in alveolar soft part sarcoma (ASPS) is orchestrated by the fusion oncoprotein, ASPSCR1-TFE3, product of a gene fusion created by a t(X;17) chromosomal translocation. Here, proteomics of proteins co-immunoprecipitating with ASPSCR1-TFE3 revealed strong enrichment of VCP/p97, an AAA+ ATPase with known segregase function. Positive and negative genetic experiments with ASPSCR1-TFE3 and VCP demonstrated that they function co-dependently for cancer cell proliferation, colony formation, enhancer activation, chromatin conformation, and transcription

2023-01-01 | GSE162478 | GEO

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