biostudies-literatureConcepcion CPAmerican Cancer SocietyKoch Institute Cancer Center SupportEPAMission Boost GrantNCI NIH HHSMemorial Sloan Kettering Cancer CenterNIH562-585https://www.ebi.ac.uk/biostudies/studies/S-EPMC8831463biostudies-literatureUnknown12(2)<i>SMARCA4</i>/<i>BRG1</i> encodes for one of two mutually exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes and is frequently mutated in human lung adenocarcinoma. However, the functional consequences of <i>SMARCA4</i> mutation on tumor initiation, progression, and chromatin regulation in lung cancer remain poorly understood. Here, we demonstrate that loss of <i>Smarca4</i> sensitizes club cell secretory protein-positive 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, <i>Smarca4</i>-deficient primary tumors lack lung lineage transcription factor activities and resemble a metastatic cCancer discovery<i>Smarca4</i> Inactivation Promotes Lineage-Specific Transformation and Early Metastatic Features in the Lung.PMC8831463P30-CA14051EP-C-17-009PF-17-009-01-CDDR01 CA216188P30 CA008748P30 CA014051MBG-18-204-01-COUNP30-CA008748R01CA216188P01 Jacks P01-CA42063P01 CA042063Kim CFMa SBhutkar AMiller MLiu MMeli KLaFave LMDeAngelo LPDel Priore IWestcott PMKRekhtman NJacks TSanchez-Rivera FJKim JYRegev ASchoenfeld AJBuenrostro JDConcepcion CPKartha VKRiely GJBronson RTRudin CMGupta Mfalse<i>Smarca4</i> Inactivation Promotes Lineage-Specific Transformation and Early Metastatic Features in the Lung.<i>SMARCA4</i>/<i>BRG1</i> encodes for one of two mutually exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes and is frequently mutated in human lung adenocarcinoma. However, the functional consequences of <i>SMARCA4</i> mutation on tumor initiation, progression, and chromatin regulation in lung cancer remain poorly understood. Here, we demonstrate that loss of <i>Smarca4</i> sensitizes club cell secretory protein-positive 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, <i>Smarca4</i>-deficient primary tumors lack lung lineage transcription factor activities and resemble a metastatic c2022-01-01T00:00:00Z2022 Feb2026-05-08T11:30:48.213Z2025-04-19T06:04:40.677ZS-EPMC88314633456124210.1158/2159-8290.cd-21-024810.1158/2159-8290.CD-21-0248