Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
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PROVIDER: PRJNA764672 | ENA |
REPOSITORIES: ENA
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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: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: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: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:In order to identify new key molecules in the pathogenesis of myxoid liposarcoma, we performed comparative gene expression profiling in myxoid liposarcoma and fat tissue samples.
2014-10-28 | GSE62747 | GEO
Project description: Not available
| S-EPMC6584455 | biostudies-literature
Project description:The FUS-DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma
| PRJNA744758 | ENA
Project description:In order to identify new key molecules in the pathogenesis of myxoid liposarcoma, we performed comparative gene expression profiling in myxoid liposarcoma and fat tissue samples. Whole genome microarray analysis was performed on eight primary myxoid liposarcoma samples and an RNA pool of eight healthy fat tissue samples.
2014-10-28 | E-GEOD-62747 | biostudies-arrayexpress
Project description:miR-135b expression is higher in myxoid liposarcoma cell lines than in adipose-derived mesenchymal cell line, as well as in myxoid liposarcoma tumors than in adjacent normal prostate tissues.To further investigate the molecular mechanisms regulated by miR-135b, we performed mRNA microarray analysis of cell cultures from myxoid liposarcoma cell line after transfections with miR-135b mimic or negative control.
2017-02-09 | GSE73347 | GEO