The FUS-DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744758 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15069500.fastq.gz | Fastqsanger.gz | |||
| SRR15069501.fastq.gz | Fastqsanger.gz | |||
| SRR15069502.fastq.gz | Fastqsanger.gz | |||
| SRR15069503.fastq.gz | Fastqsanger.gz | |||
| SRR15069504.fastq.gz | Fastqsanger.gz |
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Project description:Myxoid liposarcoma (MLS) is the second most common type of liposarcoma and is characterized by the fusion oncogene FUS‐DDIT3 or the less common EWSR1‐DDIT3. While the presence of FUS-DDIT3 as a driver oncoprotein in most MLS cases has been confirmed, the exact molecular action behind the capacity of FUS-DDIT3 for transformation is still unclear and therefore creates a challenge in finding new treatments against this type of cancer. The importance of the microenvironment for tumor progression have long been accepted and might also influence the effect of the fusion oncoprotein. However, due to a lack of relevant experimental model systems, it has been challenging to examine the microenvironmental impact in myxoid liposarcoma development. Therefore, we have developed a new model system utilizing scaffolds derived from myxoid liposarcoma patient-derived xenograft tumors that are decellularized and then repopulated with sarcoma cell lines. This cell culture system mimics in vivo-like tumor cell growth conditions and induce transcriptional changes within the cells. In order to investigate the effect of the microenvironment as well as the fusion oncogene, we analyzed myxoid liposarcoma cell lines as well as fibrosarcoma cells with and without ectopic FUS-DDIT3 expression cultured in scaffolds and adherent two-dimensional growth conditions. We identified several gene networks and processes that are uniquely associated with FUS-DDIT3 expression and with the microenvironment, respectively. The development of patient-derived scaffolds opens up new possibilities to understand tumor development.
2023-12-31 | GSE191132 | GEO
Project description:Mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes play critical roles in governing genomic architecture and gene expression and are frequently perturbed in human cancers. Transcription factors (TFs), including fusion oncoproteins, can bind to BAF complex surfaces to direct chromatin targeting and accessibility, often activating oncogenic gene loci. Here, we demonstrate that the FUS-DDIT3 fusion oncoprotein hallmark to myxoid liposarcoma (MLPS) inhibits BAF complex-mediated remodeling of adipogenic enhancer sites via sequestration of the adipogenic TF, CEBPB, from the genome. In mesenchymal stem cells, small molecule inhibition of BAF complex ATPase activity attenuates adipogenesis via failure of BAF-mediated DNA accessibility and gene activation at CEBPB target sites genome-wide. BAF chromatin targeting and gene expression profiles of FUS-DDIT3-expressing cell lines and primary tumors exhibit similarity to SMARCB1-deficient BAF loss-of-function tumor types. These data present a novel mechanism by which fusion oncoproteins generate BAF complex loss-of-function phenotypes, independent of deleterious subunit mutations.
2022-04-18 | GSE179720 | GEO
Project description:Sarcomas and leukemias that are characterized by FET (FUS, EWSR1, TAF15) fusion oncogenes consist of more than 20 entities. Myxoid liposarcoma, one of the most common FET sarcoma types, is defined by the FUS-DDIT3 or the less common EWSR1-DDIT3 fusion oncogene. Previously, JAK-STAT signaling have been connected to cancer stem cell properties and chemotherapy resistance in myxoid liposarcoma, but the role of FUS-DDIT3 is not known. Therefore, we treated HT1080 fibrosarcoma cells expression FUS-DDIT3 with JAK1/2 inhibitor ruxolitinib and performed RNA sequencing of treated and control cells. Additionally, we analyzed native HT1080 cells to be able to compare the induced gene expression changes due to FUS-DDIT3 expression with those induced by JAK-STAT pathway inhibition.
2022-01-14 | GSE149650 | GEO
Project description:Myxoid liposarcoma (MLS) is the second most common type of liposarcoma and is characterized by the fusion oncogene FUS‐DDIT3 or the less common EWSR1‐DDIT3. FUS-DDIT3 is causative in tumor development, but the molecular function of FUS-DDIT3 remains largely unknown. In addition, the tumor microenvironment is important in MLS development. However, due to a lack of relevant experimental model systems, it has been challenging to examine the microenvironmental impact in MLS development. Therefore, we have developed an in vivo-like experimental model system utilizing cell-free scaffolds derived from myxoid liposarcoma patient-derived xenograft tumors that can be repopulated with tumor cells. To study the effect of FUS-DDIT3 expression in combination with the MLS microenvironment, we analyzed MLS cell lines as well as fibrosarcoma cells with and without ectopic FUS-DDIT3 expression cultured in scaffolds using cells cultured in monolayers as reference. We identified several gene networks and processes that are uniquely associated with FUS-DDIT3 expression as well as microenvironment. The use of in vivo-like experimental systems opens new possibilities to understand tumor development and develop treatments.
2023-12-31 | GSE230773 | GEO
Project description:Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator, FUS-DDIT3 stimulates proliferation and interferes with adipogenic differentiation. As the fusion protein represents a therapeutically challenging target, a profound understanding of MLS biology is elementary to uncover FUS DDIT3-dependent molecular vulnerabilities. Recently, a specific reliance on the Hippo pathway effector and transcriptional co-regulator YAP1 was detected in MLS; however, details on the molecular mechanism of FUS-DDIT3-dependent YAP1 activation, and YAP1's precise mode of action remain unclear. In elaborate in vitro studies, employing RNA interference-based approaches, small-molecule inhibitors, and stimulation experiments with IGF-II, we show that FUS-DDIT3-driven IGF-IR/PI3K/AKT signaling promotes stability and nuclear accumulation of YAP1 via deregulation of the Hippo pathway. Co-immunoprecipitation and proximity ligation assays revealed nuclear co localization of FUS-DDIT3 and YAP1/TEAD in FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines. Transcriptome sequencing of MLS cells demonstrated that FUS DDIT3 and YAP1 co-regulate oncogenic gene signatures related to proliferation, cell cycle progression, apoptosis, and adipogenesis. In adipogenic differentiation assays, we show that YAP1 critically contributes to FUS-DDIT3-mediated adipogenic differentiation arrest. Taken together, our study provides mechanistic insights into a complex FUS-DDIT3-driven network involving IGF-IR/PI3K/AKT signals acting on Hippo/YAP1, and uncovers substantial cooperative effects of YAP1 and FUS-DDIT3 in the pathogenesis of MLS.
2022-03-28 | GSE184436 | GEO
Project description:We identified novel protein-protein interactions between FUS-CHOP, a fusion oncoprotein that drives myxoid liposarcoma, and SNF2H, the ATPase subunit of the imitation switch (ISWI) chromatin remodeling complex. We used antibodies for FUS-CHOP, SNF2H, and H3K27ac to profile localization of these proteins and histones marks on chromatin in human MLPS cell lines and show that colocalization of FUS-CHOP and SNF2H occurs at new enhancers marked by H3K27ac.
2022-02-21 | GSE145678 | GEO
Project description:A subgroup of sarcomas and leukemias is defined by characteristic FET (FUS, EWSR1, TAF15) fusion oncogenes. Myxoid liposarcoma (MLS) and Ewing sarcoma (EWS) are the most common entities characterized by the fusion oncogenes FUS-DDIT3 and EWSR1-FLI1, respectively. Here, we performed ATAC-Seq on the cell lines MLS 1765-92 and EWS TC-71 to characterize and compare their chromatin landscape.
2025-09-22 | GSE235218 | GEO
Project description:Myxoid liposarcoma (MLS) is a rare tumor type generally occuring in deep soft tissues. Genetically, it is characterized by the FUS-DDIT3 fusion oncogene with few additional mutations. MLS 402-91 is one of few existing MLS cell lines. The purpose of this dataset is to study the variation in gene expression in MLS at the single-cell level.
2025-09-22 | GSE248661 | GEO
Project description:Some specific sarcomas and leukemias are defined by characteristic FET (FUS, EWSR1, TAF15) fusion oncogenes. Myxoid liposarcoma and Ewing sarcoma are the most common entities characterized by FUS-DDIT3 and EWSR1-FLI1, respectively. Here, we performed whole transcriptome analysis of HT1080 cells with either ectopic FUS-DDIT3 or ectopic EWSR1-FLI1 expression.
2019-03-12 | GSE125941 | GEO
Project description:Myxoid liposarcoma is one of the most common sarcoma entities characterized by FET fusion oncogenes. Despite a generally favorable prognosis of myxoid liposarcoma, chemotherapy resistance remains a clinical problem. This cancer stem cell property is associated with JAK-STAT signaling, but the link to the myxoid-liposarcoma-specific FET fusion oncogene FUS-DDIT3 is not known. Here, we show that ectopic expression of FUS-DDIT3 resulted in elevated levels of STAT3 and phosphorylated STAT3. RNA sequencing identified 126 genes that were regulated by both FUS-DDIT3 expression and JAK1/2 inhibition using ruxolitinib. Sixty-six of these genes were connected in a protein interaction network. Fifty-three and 29 of these genes were confirmed as FUS-DDIT3 and STAT3 targets, respectively, using public chromatin immunoprecipitation sequencing data sets. Enriched gene sets among the 126 regulated genes included processes related to cytokine signaling, adipocytokine signaling, and chromatin remodeling. We validated CD44 as a target gene of JAK1/2 inhibition and as a potential cancer stem cell marker in myxoid liposarcoma. Finally, we showed that FUS-DDIT3 interacted with phosphorylated STAT3 in association with subunits of the SWI/SNF chromatin remodeling complex and PRC2 repressive complex. Our data show that the function of FUS-DDIT3 is closely connected to JAK-STAT signaling. Detailed deciphering of molecular mechanisms behind tumor progression opens up new avenues for targeted therapies in sarcomas and leukemia characterized by FET fusion oncogenes.
| S-EPMC8851354 | biostudies-literature