Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung [Bulk RNA-seq]

ABSTRACT: SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 alterations on lung cancer initiation and progression remain poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient tumors lack lung lineage transcription factor activities and instead show activation of embryonic stem cell-like programs, resembling a metastatic cell state. Thus, the SWI/SNF complex – via Smarca4 – acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.

ORGANISM(S): Mus musculus

PROVIDER: GSE180817 | GEO | 2021/09/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung [scATAC-seq]

Project description:SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 alterations on lung cancer initiation and progression remain poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient tumors lack lung lineage transcription factor activities and instead show activation of embryonic stem cell-like programs, resembling a metastatic cell state. Thus, the SWI/SNF complex – via Smarca4 – acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.

2021-09-07 | GSE161920 | GEO

Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung [CUT&RUN]

Project description:SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 mutation on tumor initiation, progression and chromatin regulation in lung cancer remains poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung in a cell-type dependent fashion to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and instead show hyper-activation of embryonic stem cell-like programs, resembling a metastatic cell state. Mechanistically, we show that all three classes of SWI/SNF complexes are unable to bind and open chromatin at distinct regulatory regions in the absence of SMARCA4, thereby preventing lineage factors from binding to their targets and maintaining cell identity – ultimately accelerating tumor progression. Thus, the SWI/SNF complex – via Smarca4 – acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.

2021-09-07 | GSE164820 | GEO

Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung [RNA-seq]

2021-09-07 | GSE164770 | GEO

Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung [ATAC-seq]

2021-09-07 | GSE164857 | GEO

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Project description:Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance seen in 10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify SWI/SNF subunits that are deregulated in NEPC, demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease and that SMARCA4 depletion impairs prostate cancer cell growth. We also show that SWI/SNF complexes interact with different lineage-specific factors in prostate adenocarcinoma and in NEPC cells, and that induction of lineage plasticity through depletion of REST is accompanied by changes in SWI/SNF genome occupancy. These data suggest a specific role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

2020-11-04 | PXD016861 | Pride

Gene expression profiling on isogenic lines expressing wild-type and mutant forms of SMARCA2 and SMARCA4

Project description:SMARCA2 and SMARCA4 are two mutually exclusive ATPase subunits of SWI/SNF complex. SMARCA4 deficient lung cancer population selectively depend on SMARCA2 for cancer growth phenotype. Rescue experiments with ectopic expression of wild-type, bromodomain mutant and ATPase dead SMARCA2 and SMARCA4 highlight that ATPase domain is the drug target. In this study, we performed genome-wide microarray and differential gene expression profiling on isogenic lung cancer lines expressing cDNA rescue constructs for wild-type, bromodomain mutant and ATPase dead SMARCA2 and SMARCA4

2015-07-21 | GSE69088 | GEO

siRNA Knockdown of SWI/SNF complex proteins in prostate cancer cell lines

Project description:Here we performed transcriptional profiling of the prostate cancer cell lines LNCaP and 22Rv1 comparing non-targeting siRNA treatment versus siRNAs targeting SWI/SNF complex proteins (SMARCA2, SMARCA4, and SMARCB1). Goal was to determine the effect of SWI/SNF knockdown on gene expression in prostate cancer. Two-condition experiment: non-targeting siRNA versus SWI/SNF-siRNA treated cells. Three SWI/SNF proteins were targeted: SMARCA2, SMARCA4, and SMARB1. Biological replicates: 1 control replicate, 2 treatment replicates per SWI/SNF protein. Technical replicates: 1 replicate per SWI/SNF protein. Cell lines: 22Rv1 and LNCaP.

2013-07-20 | E-GEOD-40384 | biostudies-arrayexpress

SMARCA4 loss is synthetic lethal with CDK4/6 via restriction CCND1 chromatin accessibility in lung cancer

Project description:Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, is frequently inactivated in cancers which is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA2/4 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.

2019-01-03 | GSE121755 | GEO

The SWI/SNF complex regulates the expression of miR-222, a tumor suppressor microRNA in lung adenocarcinoma

Project description:Mammalian SWI/SNF complexes are considered as key epigenetic regulators and they are recurrently mutated in many types of cancer. Most of the studies of these chromatin remodeling complexes are focused on their role in regulating protein-coding genes. However, here we show that the SWI/SNF complex is able to control the expression of microRNAs. We used a SMARCA4-deficient model of lung adenocarcinoma where we could track changes of the miRNome upon SMARCA4 restoration. We found that exogenous SMARCA4 was successfully incorporated into endogenous SWI/SNF complexes and that these SMARCA4-SWI/SNF complexes induced significant changes in the expression of cancer-related microRNAs. The most significantly dysregulated miRNA was miR-222, whose expression was promoted by SMARCA4-SWI/SNF complexes but not by SMARCA2-SWI/SNF complexes via their direct binding to a miR-222 enhancer region. Importantly, miR-222 expression decreased cell viability and impaired cell clonogenicity, phenocopying the tumor-suppressor role of the SMARCA4-SWI/SNF complex in lung cancer. Finally, we showed that the miR-222 enhancer does not interact with any cancer-related protein-coding genes, supporting that its tumor suppressor effect may be exerted via miR-222. Overall, this study highlights the relevant role of the SWI/SNF complex in regulating the expression of the non-coding genome.

2021-07-20 | GSE167140 | GEO

Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung

Project description:Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung

| PRJNA692226 | ENA