FUS-CHOP and ISWI chromatin remodeling in human myxoid liposarcoma
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ABSTRACT:
PROVIDER: PRJNA607943 | ENA |
REPOSITORIES: ENA
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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:Identification of differential gene regulation pattern in human liposarcoma The FUS-CHOP fusion protein has been found to be instrumental for specific oncogenic processes in liposarcoma, but its ability to induce metastasis and the underlying mechanisms by which this can be achieved remain unknown. In order to dissect its functional role in this context, we stably overexpressed this protein in SW872 liposarcoma and HT1080 fibrosarcoma cell lines, and were able to demonstrate that forced expression of FUS-CHOP significantly increases migration and invasion, as well as enhance lung and liver metastasis in the in vivo chicken chorioallantoic membrane (CAM) model, that is proliferation independent. Additionally, FUS-CHOP enhances the expression of matrix-metalloproteinases -2 and -9, and transactivates their promoters in vitro. Mutational analysis showed that C/EBP-β- (-769/-755), NF-κB (-525/-516) and CREB/AP-1 (-218/-207) sites were important for MMP-2, and NF-κB (-604/-598), AP-1 (-539/-532) and AP-1 (-81/-72) for MMP-9 transactivation. Moreover, a direct in vivo interaction of FUS-CHOP was observed in case of the MMP-2 promoter within region (-769/-207). siRNA data revealed that MMP-2 expression is essential in the FUS-CHOP induced metastatic phenotype. MMP-2-mRNA and protein expression correlated significantly with FUS-CHOP positivity in 31 resected patient liposarcoma tissues. We have for the first time provided substantial evidence for the FUS-CHOP oncoprotein as an inducer of metastasis that is due to the transcriptional induction of specific tumor-associated proteases. Insights gained from this study not only support a deeper understanding of the mechanistic properties of FUS-CHOP, but also open up new avenues for targeted therapy. 3 liposarcoma tumor samples, 3 corresponding normal samples, one sample replicated
2013-09-20 | E-GEOD-51049 | biostudies-arrayexpress
Project description:Transcriptional profiling of patient-derived xenograft models of myxoid liposarcoma with either FUS-CHOP type I, named as ML017, or FUS-CHOP type III, named as ML006. Both ML017 and ML006 are responsive to trabectedin treatment, while model ML017/ET has aquired resistance to the drug. Samples are either under untreated conditions, or treated either with trabectedin or pioglitazone or both.
2020-01-10 | E-MTAB-8632 | biostudies-arrayexpress
Project description:Identification of differential gene regulation pattern in human liposarcoma The FUS-CHOP fusion protein has been found to be instrumental for specific oncogenic processes in liposarcoma, but its ability to induce metastasis and the underlying mechanisms by which this can be achieved remain unknown. In order to dissect its functional role in this context, we stably overexpressed this protein in SW872 liposarcoma and HT1080 fibrosarcoma cell lines, and were able to demonstrate that forced expression of FUS-CHOP significantly increases migration and invasion, as well as enhance lung and liver metastasis in the in vivo chicken chorioallantoic membrane (CAM) model, that is proliferation independent. Additionally, FUS-CHOP enhances the expression of matrix-metalloproteinases -2 and -9, and transactivates their promoters in vitro. Mutational analysis showed that C/EBP-β- (-769/-755), NF-κB (-525/-516) and CREB/AP-1 (-218/-207) sites were important for MMP-2, and NF-κB (-604/-598), AP-1 (-539/-532) and AP-1 (-81/-72) for MMP-9 transactivation. Moreover, a direct in vivo interaction of FUS-CHOP was observed in case of the MMP-2 promoter within region (-769/-207). siRNA data revealed that MMP-2 expression is essential in the FUS-CHOP induced metastatic phenotype. MMP-2-mRNA and protein expression correlated significantly with FUS-CHOP positivity in 31 resected patient liposarcoma tissues. We have for the first time provided substantial evidence for the FUS-CHOP oncoprotein as an inducer of metastasis that is due to the transcriptional induction of specific tumor-associated proteases. Insights gained from this study not only support a deeper understanding of the mechanistic properties of FUS-CHOP, but also open up new avenues for targeted therapy.
2013-09-20 | GSE51049 | 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. 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:MicroRNAs (miRNAs, miRs) are small noncoding RNAs, which control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumor suppressor genes, play important roles in carcinogenesis. Myxoid liposarcomas (MLS) are characterized by t(12;16)(q13;p11) translocation and expression of TLS/CHOP chimeric transcripts (various types) which encode different oncogenic proteins. TLS-CHOP is important for the molecular mechanisms in the development of MLS, but the involvement in microRNA expression still remain poorly understood. Thus we explored the target microRNA of TLS-CHOP influence cell-proliferation or cell death with microarray. MicroRNAs (miRNAs, miRs) are small noncoding RNAs, which control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumor suppressor genes, play important roles in carcinogenesis. Myxoid liposarcomas (MLS) are characterized by t(12;16)(q13;p11) translocation and expression of TLS/CHOP chimeric transcripts (various types) which encode different oncogenic proteins. TLS-CHOP is important for the molecular mechanisms in the development of MLS, but the involvement in microRNA expression still remain poorly understood. In this study, we have found that miR-486-5p (miR-486) expression level was downregulated by ectopic expression of TLS-CHOP fusion gene in mouse fibroblast cells (NIH3T3). In addition, we found overexpression of miR-486 inhibited the cell growth in the 2645/94 cells and in situ hybridization of miR-486 showed MLS tissues had lower signal intensity compared with non-tumor tissues. Thus we explored the target genes of miR-486 influence cell-proliferation or cell death with microarray. We compared the microRNA profiles of cells treated with TLS-CHOP or empty vector about NIH-3T3 cell-line. We compared the whole mRNA profiles of cells transfected with miR-486 oligonucleotides or control oligo about myxoid liposarcoma cell-line.
2013-03-23 | E-GEOD-36966 | biostudies-arrayexpress
Project description:The TLS-CHOP fusion protein is found in the majority of human myxoid liposarcomas (MLS), and is thought to have oncogenic functions. Until now, however, the molecular function of TLS-CHOP for oncogenesis is still elusive. In this report, we have revealed that knockdown of TLS-CHOP by specific siRNA in MLS-derived cell lines inhibits cell growth and leads to cell death. Thus, TLS-CHOP may be a promising therapeutic target for MLS treatment. Thus we explored the target genes of TLS-CHOP influence cell-proliferation or cell death with microarray. We compared the whole mRNA profiles of cells treated with TLS-CHOP siRNA or control oligo in two myxoid liposarcoma cell-line.
2013-12-27 | E-GEOD-33616 | biostudies-arrayexpress
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:FUS-CHOP and EWS-CHOP balanced translocations characterize myxoid liposarcoma which encompasses myxoid (ML) and round cell (RC) variants initially believed to be distinct diseases. Currently, myxoid and RC liposarcoma are regarded to represent the well differentiated and the poorly differentiated ends, respectively, within spectrum of myxoid liposarcoma where the fusion proteins blocking lipogenic differentiation play a role in tumor initiation while molecular determinants associated to progression to RC remain poorly understood. Activation of AKT pathway sustained by PIK3CA and PTEN mutations and growth factor receptor signalling such as RET and IGF1R have been recently correlated with the increasing of aggressiveness and RC. Aim of the present study is to elucidate molecular events involved in driving round cell progression analyzing two small series of MLS selected to be representative of the two end of the gamut: the pure myxoid (0% of RC component) and RC with high cellular component (≥80%).
2014-10-30 | GSE55465 | GEO