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Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ChIP-Seq]

ABSTRACT: Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ChIP-Seq]

PROVIDER: PRJNA1183853 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31293800_1.fastq.gz	Fastqsanger.gz
	SRR31293800_2.fastq.gz	Fastqsanger.gz
	SRR31293801_1.fastq.gz	Fastqsanger.gz
	SRR31293801_2.fastq.gz	Fastqsanger.gz
	SRR31293802_1.fastq.gz	Fastqsanger.gz

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Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ATAC-Seq]

Project description:Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ATAC-Seq]

| PRJNA1183856 | ENA

Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ChIP-Seq]

Project description:Dysfunction of epigenetic modulators such as the SWI/SNF complex is involved in a wide spectrum of cancer entities, yet their precise role in carcinogenesis is not clear to date Among SWI/SNF-mutant entities, SMARCB1-deficient cancers such as Epithelioid Sarcoma (EpS) are characterized by this genetic event in an otherwise rather silent mutational landscape. However, its oncogenic role remains unclear. Here, we generate a panel of SMARCB1 re-expressing Epithelioid Sarcoma (EpS) cell lines and employ a functional multi-omics approach to characterize and compare the function of the residual SMARCB1-deficient and the physiological SWI/SNF complex in EpS. We show that SWI/SNF holds canonical characteristics of both tumor-suppressors and proto-oncogenes due to its multi-faceted role in the regulation of the epigenome. Our data indicates that the loss of SMARCB1 causes an overall loss of SWI/SNF chromatin affinity at cis-regulatory enhancer elements, inducing a preference for uncontrolled proliferation and cell cycle progression as opposed to development and differentiation. As epigenetic regulation is a dynamic complex, we further demonstrate that EpS cell lines depend on continuous residual SWI/SNF action to maintain clonogenicity and proliferation. Consequently, our models exhibit markedly increased sensitivity to pharmacological inhibition of the residual SWI/SNF when compared with SWI/SNF-proficient cancer entities. Collectively, our results shed new light on the pleiotropic, deregulated pathways upon SWI/SNF dysfunction in EpS and provide inroads for further therapeutic approaches.

2024-11-09 | GSE281436 | GEO

Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma [ATAC-Seq]

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Characterizing the function of SMARCB1 deficient and proficient SWI/SNF in Epithelioid Sarcoma cell lines by tetON re-expression and small molecule inhibition (BRM014)

Project description:Several isogenic tetON SMARCB1 re-expressing Epithelioid Sarcoma cell lines alongside bulk empty (MCS) vector transduced controls were submitted to DOX (re-expression) and BRMO014 (inhibition of SWI/SNF)

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Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Project description:We report the expression profiles of 21 T- and NK-cell lymphomas to provide a platform for further investigation of targetable vulnerabilities in diseases represented by these cell lines

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Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes

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Project description:Myelofibrosis (MF) is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. MF patients frequently carry driver mutations in JAK2 and Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across MF patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three therapeutic vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high MAPK-Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high ER stress, responding to ER stressors and UPR inhibition. Overall, our integrated analyses provide a molecularly-motivated roadmap for individualized MF patient treatment.

2023-10-12 | PXD036075 | Pride

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Project description:Genetic screens reveal new targetable vulnerabilities in BAP1-deficient Mesothelioma

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Project description:DOX-dependently SMARCB1-re-expressing, stable isogenic EpS cell line models were generated and submitted to global proteomic analysis as well as interactome analysis by co-immunoprecipitation of BRG1, one of the SWI/SNF core ATPases after 96h of DOX treatment.

2024-12-17 | PXD053945 | Pride

A quality control factor for chromatin complexes is synthetic lethal in SMARCB1-mutant cancers

Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and is problematic because the tumor suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. Here, we report that the little-studied gene DDB1-CUL4 Associated Factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and promotes degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. Upon depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore SWI/SNF-mediated gene expression to levels sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality control factors may effectively reverse the malignant state of some cancers driven by disruption of tumor suppressor complexes.

2024-01-21 | PXD046275 | Pride

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