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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. We used microarrays to detail the global program of gene expression in mouse and human ASPS cells.
2023-01-20 | GSE186789 | GEO
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.
2023-01-20 | GSE215316 | GEO
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. We used microarrays to detail the global program of gene expression in mouse and human ASPS cells.
2023-01-20 | GSE215264 | GEO
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.
2023-01-16 | GSE189163 | GEO
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
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.
2024-04-19 | GSE235737 | GEO
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.
2024-04-19 | GSE235738 | GEO
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.
2024-04-19 | GSE255962 | GEO
Project description:PurposeAlveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs).Patients and methodsWe conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging.ResultsOf 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis.ConclusionIn this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.
| S-EPMC3677840 | biostudies-literature
Project description:Alveolar soft part sarcoma (ASPS) is a rare, hypervascular soft tissue sarcoma with a low chemotherapy response rate. Here, we report an ASPS case with multiple lung metastases on initial presentation. The primary tumor, a hypervascular soft tissue mass 4.1×3.2×2.0 cm, located in the right thigh, was resected prior to chemotherapy. The patient suffered disease progression after two cycles of gemcitabine-docetaxel treatment. Immunohistochemical examination of the tumor tissue revealed strong positive staining for vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2). The patient was subsequently treated with apatinib (500 mg/day), a specific VEGFR-2 inhibitor. Treatment was well tolerated, and the patient exhibited a partial response, with the lung metastases reduced in size and number after one month of therapy. To date, 12-month progression-free survival has been achieved. Apatinib may provide an additional treatment option for metastatic ASPS, particularly in cases resistant to other chemotherapeutic options. Furtherstudies with more cases with longer follow-up times will be necessary to determine the clinical efficacy of apatinib for treatment of ASPS.
| S-EPMC5564851 | biostudies-other