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Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (ChIP-Seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE241370 | GEO | 2023/10/19

REPOSITORIES: GEO

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Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (RNA-Seq)

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

Gene expression profiles of mouse CIC-DUX4 sarcoma

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.

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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.

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The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein.

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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.

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