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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE164867 | GEO | 2021/09/07

REPOSITORIES: GEO

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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.

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

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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.

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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

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

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