Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genetic Screen in a Pre-Clinical Model of Sarcoma Development Defines Drivers and Therapeutic Vulnerabilities

ABSTRACT: High-grade complex karyotype sarcomas are a heterogeneous group of more than seventy tumors that vary in histology, clinical course, and patient demographics. Despite these differences, these high-grade sarcomas are treated similarly with varying outcomes. Pre-clinical models of distinct human sarcoma subtypes would advance insights into the relationships between sarcomas and inform therapeutic decisions. We describe the transformation of human mesenchymal stem cells into multiple subtypes of high-grade sarcoma. Using a pooled genetic screening approach, we identified key drivers and potential modifiers of transformation. YAP1, KRAS, CDK4, and PIK3CA were validated as drivers of four distinct sarcoma subtypes, undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), leiomyosarcoma (LMS), and osteosarcoma (OS). Histologically and phenotypically these tumors reflect human sarcomas including the pathognomonic complex karyotype and YAP1 amplification. Transcriptome analysis confirmed that these tumors accurately recapitulate human disease. This model is a tool that can be used to begin to understand pathways and mechanisms driving human sarcoma development, the relationship between sarcoma subtypes and to identify and test new therapeutic targets for this aggressive and heterogeneous disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228213 | GEO | 2024/08/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Dual Pten/p53 suppression enhances Notch signaling and sarcoma progression

Project description:Soft tissue sarcomas (STS) are a heterogeneous group of tumors associated with poor clinical outcome. While a subset of STS are characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and p53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas (HGUPS), leiomyosarcomas (LMS) and carcinosarcomas (CS) that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient whereas the wild-type allele of p53 invariably gained point mutations. Gene expression profile showed upregulated Notch signaling in PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ tumors compared to Pten+/+p53M-bM-^HM-^F/+. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of p53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells, while activating the Notch pathway. Moreover, the increased oncogenic behavior of PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ and shPten-transduced Pten+/+p53M-bM-^HM-^F/+ tumor cells was counteracted by treatment with a gamma secretase inhibitor (GSI), suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and p53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the crosstalk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying high-grade sarcoma patients for targeted treatments. Compare PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ to Pten+/+p53M-bM-^HM-^F/+ high-grade undifferentiated pleomorphic sarcomas (HGUPS) 4 PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ were compared to 5 Pten+/+p53M-bM-^HM-^F/+ Keywords: Differential gene expression.

2013-01-01 | E-GEOD-42103 | biostudies-arrayexpress

Dual Pten/p53 suppression enhances Notch signaling and sarcoma progression

Project description:Soft tissue sarcomas (STS) are a heterogeneous group of tumors associated with poor clinical outcome. While a subset of STS are characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and p53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas (HGUPS), leiomyosarcomas (LMS) and carcinosarcomas (CS) that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient whereas the wild-type allele of p53 invariably gained point mutations. Gene expression profile showed upregulated Notch signaling in Pten∆/+p53∆/+ tumors compared to Pten+/+p53∆/+. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of p53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells, while activating the Notch pathway. Moreover, the increased oncogenic behavior of Pten∆/+p53∆/+ and shPten-transduced Pten+/+p53∆/+ tumor cells was counteracted by treatment with a gamma secretase inhibitor (GSI), suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and p53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the crosstalk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying high-grade sarcoma patients for targeted treatments. Compare Pten∆/+p53∆/+ to Pten+/+p53∆/+ high-grade undifferentiated pleomorphic sarcomas (HGUPS)

2013-01-01 | GSE42103 | GEO

Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas [methylation]

Project description:We used the Infinium HumanMethylation27 platform to profile DNA methylation in 80 primary, untreated high-grade soft tissue sarcomas, representing eight relevant subtypes, two non-neoplastic fat samples and 14 representative sarcoma cell lines. Marcus, Renner

2013-11-16 | E-GEOD-52391 | biostudies-arrayexpress

Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas [gene expression]

Project description:We used the Infinium HumanHT-12 platform to profile gene expression in 79 primary, untreated high-grade soft tissue sarcomas, representing eight relevant subtypes, two non-neoplastic fat samples and 13 representative sarcoma cell lines. Marcus, Renner

2013-11-16 | E-GEOD-52390 | biostudies-arrayexpress

Project description:Genetic Screen in a Pre-Clinical Model of High-Grade Complex Karyotype Sarcoma Identifies Drivers of Distinct Sarcoma Subtypes

| PRJNA948835 | ENA

Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas [methylation]

2013-11-16 | GSE52391 | GEO

Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas [gene expression]

2013-11-16 | GSE52390 | GEO

Discovery-Based Protein Expression Profiling Identifies Distinct Subgroups and Pathways in Leiomyosarcomas

Project description:20 tumor samples run in duplicates, consisting of pleomorphic sarcomas; classfied as leiomyosarcoma or high-grade undifferentiated pleomorphic sarcoma.

2020-01-27 | PXD000616 | Pride

Super-enhancer analysis of human sarcomas reveals YAP1 control of NF-κB-dependent tumorigenesis [ChIP-seq]

Project description:Recent sequencing efforts have failed to identify consistent oncogenic driver mutations in most adult soft tissue sarcomas. Therefore, we investigated alternate genetic/epigenetic mechanisms underlying sarcomagenesis to facilitate development of novel therapeutics. Our previous work showed that deregulation of the Hippo pathway increases proliferation in many types of sarcoma. We have now identified the mechanism of Hippo-mediated sarcomagenesis using autochthonous mouse models, ChIP-seq (H3K27Ac) and super-enhancer (SE) analysis of human undifferentiated pleomorphic sarcoma (UPS), an aggressive muscle-derived tumor. We found that the Hippo effector, Yes-Associated Protein 1 (YAP1) enhances NF-êB signaling and that YAP1 is constitutively active in these tumors due to epigenetic silencing of its inhibitor Angiomotin (AMOT). Treatment with epigenetic modulators (SAHA and JQ1) inhibited YAP1 transcription and restored expression of AMOT. These changes initiated a muscle differentiation program and reduced tumorigenesis.

2018-03-01 | GSE97295 | GEO

Super-enhancer analysis of human sarcomas reveals YAP1 control of NF-κB-dependent tumorigenesis [RNA-seq]

2018-03-01 | GSE97296 | GEO