Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA356548 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Although a few ancillary markers have been used in the differential diagnosis of CDS, additional CDS-specific biomarkers are needed in challenging diagnosis for a more definitive classification. Here we have generated an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMCs) with human CIC-DUX4 cDNA. The recipient mice transplanted with eMCs expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small round to short spindle cells. Gene expression profiles of CDS and eMCs revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh and Zic1. Immunohistochemical analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2, that are upregulated in CDS, effectively inhibited tumor growth in vitro. Palbociclib, a CDK4/6 inhibitor, also showed growth inhibition of mouse CDS cells in vitro, while trabectedin induced tumor suppressive effects both in vitro and in vivo. In summary, the CDS mouse model provides important biological information of CDS and is a useful platform to explore novel biomarkers and therapeutic agents for CDS. We used microarrays to detail the global program of gene expression in mouse CDS.
2017-06-21 | GSE90978 | GEO
Project description:CIC-DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies is limited by the scarcity of tissues and patients. To minimize, we made three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three models developed spontaneous tumors and widespread metastasis in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic CIC function and loxP site proximity. Characterization of primary and metastatic mouse tumors showed that they consistently expressed the CIC-DUX4 fusion protein as well as other downstream markers of the disease authenticating them as CDS. Lastly, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-seq maps, validate CIC-DUX4 as a neomorphic transcriptional activator and point to ETS family transcription factors as cooperative and redundant drivers of the core regulatory circuitry.
2023-10-19 | GSE241370 | GEO
Project description:CIC-DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies is limited by the scarcity of tissues and patients. To minimize, we made three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three models developed spontaneous tumors and widespread metastasis in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic CIC function and loxP site proximity. Characterization of primary and metastatic mouse tumors showed that they consistently expressed the CIC-DUX4 fusion protein as well as other downstream markers of the disease authenticating them as CDS. Lastly, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-seq maps, validate CIC-DUX4 as a neomorphic transcriptional activator and point to ETS family transcription factors as cooperative and redundant drivers of the core regulatory circuitry.
2023-10-19 | GSE241369 | GEO
Project description:The concept of Ewing family of tumors (EFT), characterized by FET-ETS fusions, has been recently challenged by the description of Ewing-like tumors with different gene fusions. Here we investigate the similarities and differences of FET-ETS, BCOR-CCNB3, CIC-DUX4 and EWSR1-NFATc2 tumors samples with a number of other sarcomas. Unsupervised clustering of gene expression profiles fully discriminates these four molecular entities. Specific gene signatures and pathways were further validated in model cell lines. While a clear inflammatory signature characterizes EWSR1-NFATc2 tumors, BCOR-CCNB3 and CIC-DUX4 exhibit high expression of homeobox and ETS protein families, respectively. We strongly suggest that abnormalities of chromatin remodeling may gather CIC-DUX4 and BCOR-CCNB3 tumors with rhabdoid tumors and synovial sarcomas. This dataset conains 14 CIC-DUX4 and 7 EWSR1-NFATc2 tumor samples as well as Human mesenchymal cell line expressing EWSR1-NFATc2 (duplicates) or mock treated (duplicates) and IB120 CIC-DUX4 cell line expressing an shRNA directed against CIC-DUX4 (4 replicates) or mock treated (duplicates).
2015-06-30 | E-GEOD-60740 | biostudies-arrayexpress
Project description:CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding properties, and is therefore believed to function as an aberrant transcription factor. However, the chromatin remodeling events induced by CIC-DUX4 are not well understood, limiting our ability to identify new mechanism-based therapeutic strategies for these patients. Here we generated a genome wide profile of CIC-DUX4 DNA occupancy and associated chromatin states in human CDS cell models and primary tumors. Combining chromatin profiling, proximity ligation assays, as well as genetic and pharmacological perturbations, we show that CIC-DUX4 operates as a potent transcriptional activator at its binding sites. This property is in contrast with the repressive function of the wild type CIC protein, and is mainly mediated through the direct interaction of CIC-DUX4 with the acetyltransferase p300. In keeping with this, we show p300 to be essential for CDS tumor cell proliferation, and its pharmacological inhibition to significantly impact tumor growth in vitro andin vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation and suggests a potential therapeutic approach for the clinical management of CDS patients.
2024-01-31 | GSE248040 | GEO
Project description:A recently identified pediatric subtype of undifferentiated round cell sarcoma that is driven by fusion between the cell cycle regulator and transcriptional repressor, capicula (CIC) and the transcriptional activator, DUX4 has been identified based on its histology, clinical differences, and aggressiveness. Because CIC-DUX4 acquires the p300-interacting activation domain of DUX4, we hypothesized that its transcriptional activation potential, and thus the oncogenicity of CIC-DUX4, would require p300 or its homologues, CBP. Recently, a new class of histone acetyltransferase inhibitors with high selectivity for p300 and CBP has been described, and two compounds, A-485, and iP300w, have been shown to inhibit p300 and CBP both in vitro and in vivo with iP300w having the ability to reverse gene expression changes caused by DUX4. If this hypothesis is correct, iP300w should potently counteract the CIC-DUX4 gene expression program and might be a particularly effective therapy for CDS. In this study, we confirm this hypothesis, demonstrating that CIC-DUX4 requires p300/CBP for its activity. We also demonstrate that CIC-DUX4 induces a global increase in H3 acetylation, like DUX4, which is reversible with iP300w treatment. We find that CIC-DUX4 activity is potently blocked by iP300w, and that this compound has potent activity against CDS cell lines and in an in vivo cancer xenograft assay.
2021-10-21 | GSE165729 | GEO
Project description:Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.
2024-10-16 | GSE279546 | GEO
Project description:Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.
2024-06-06 | GSE269295 | GEO
Project description:CIC::DUX4 sarcoma (CDS) is a lethal cancer driven by a fusion between tumor suppressor Capicua (CIC) and pioneer transcription factor double homeobox 4 (DUX4). To develop an immunocompetent pre-clinical model of CDS, we previously generated three genetically engineered mouse models (GEMMs) of CDS with CIC::DUX4 regulated by loxP-STOP-loxP cassettes. However, all three models developed spontaneous tumors without Cre recombinase. Here, we established an innovative GEMM of CDS (dFLEx CDS) that employs a dual recombinase (Cre + FLPE) FLEx-switch design to activate CIC::DUX4 expression and initiate sarcomagenesis in a spatially and temporally-controlled manner. Because CIC::DUX4 drives sarcoma development by activating a distinct oncogenic transcriptional program, we performed a drug screen on human-derived CDS cell lines using a library of compounds that modulate transcriptional regulation. This screen identified Minnelide, an inhibitor of RNA polymerase II-mediated transcription, as a selective inhibitor of CDS. Mechanistically, Minnelide acted through xeroderma pigmentosum type B to alter phosphorylation of RPB1, the largest subunit of RNA polymerase II. Subsequently, RPB1 underwent degradation leading to apoptosis of CDS cells. Minnelide demonstrated in vivo efficacy in autochthonous dFLEx CDS GEMMs and in human CDS xenografts. As Minnelide has already been demonstrated to be safe in clinical trials with activity for adult cancers, these findings nominate Minnelide as a novel therapeutic option to test in CDS patients.
2026-05-20 | GSE328406 | GEO
Project description:CIC::DUX4 sarcoma (CDS) is a lethal cancer driven by a fusion between tumor suppressor Capicua (CIC) and pioneer transcription factor double homeobox 4 (DUX4). To develop an immunocompetent pre-clinical model of CDS, we previously generated three genetically engineered mouse models (GEMMs) of CDS with CIC::DUX4 regulated by loxP-STOP-loxP cassettes. However, all three models developed spontaneous tumors without Cre recombinase. Here, we established an innovative GEMM of CDS (dFLEx CDS) that employs a dual recombinase (Cre + FLPE) FLEx-switch design to activate CIC::DUX4 expression and initiate sarcomagenesis in a spatially and temporally-controlled manner. Because CIC::DUX4 drives sarcoma development by activating a distinct oncogenic transcriptional program, we performed a drug screen on human-derived CDS cell lines using a library of compounds that modulate transcriptional regulation. This screen identified Minnelide, an inhibitor of RNA polymerase II-mediated transcription, as a selective inhibitor of CDS. Mechanistically, Minnelide acted through xeroderma pigmentosum type B to alter phosphorylation of RPB1, the largest subunit of RNA polymerase II. Subsequently, RPB1 underwent degradation leading to apoptosis of CDS cells. Minnelide demonstrated in vivo efficacy in autochthonous dFLEx CDS GEMMs and in human CDS xenografts. As Minnelide has already been demonstrated to be safe in clinical trials with activity for adult cancers, these findings nominate Minnelide as a novel therapeutic option to test in CDS patients.
2026-05-20 | GSE328405 | GEO