{"doi":"10.1158/2159-8290.c.6549551","title":"Data from <i>Smarca4</i> Inactivation Promotes Lineage-Specific Transformation and Early Metastatic Features in the Lung","abstract":"<div>Abstract<p><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 cell state. Mechanistically, we show that <i>Smarca4</i> loss impairs the function of all three classes of SWI/SNF complexes, resulting in decreased chromatin accessibility at lung lineage motifs and ultimately accelerating tumor progression. Thus, we propose that the SWI/SNF complex via <i>Smarca4</i> acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.</p>Significance:<p>We demonstrate cell-type specificity in the tumor-suppressive functions of SMARCA4 in the lung, pointing toward a critical role of the cell-of-origin in driving SWI/SNF-mutant lung adenocarcinoma. We further show the direct effects of SMARCA4 loss on SWI/SNF function and chromatin regulation that cause aggressive malignancy during lung cancer evolution.</p><p><i>This article is highlighted in the In This Issue feature, p. 275</i></p></div>","journal":null,"year":2023,"id":4238,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0735,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-04-04","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":3622,"name":"Sai Ma","orcid":"0000-0002-9785-7929","position":1,"is_corresponding":false},{"id":7639,"name":"Lindsay M. LaFave","orcid":"0000-0002-5203-4961","position":2,"is_corresponding":false},{"id":75638,"name":"Arjun J. Bhutkar","orcid":null,"position":3,"is_corresponding":false},{"id":39873,"name":"Manyuan Liu","orcid":null,"position":4,"is_corresponding":false},{"id":39874,"name":"Lydia P. DeAngelo","orcid":"0000-0002-0549-325X","position":5,"is_corresponding":false},{"id":17251,"name":"Jonathan Y. Kim","orcid":null,"position":6,"is_corresponding":false},{"id":16050,"name":"Isabella Del Priore","orcid":"0000-0002-9665-1101","position":7,"is_corresponding":false},{"id":39875,"name":"Adam J. Schoenfeld","orcid":"0000-0002-2644-1416","position":8,"is_corresponding":false},{"id":39876,"name":"Manon Miller","orcid":null,"position":9,"is_corresponding":false},{"id":7644,"name":"Vinay K. Kartha","orcid":"0000-0002-2160-2196","position":10,"is_corresponding":false},{"id":16054,"name":"Peter M.K. Westcott","orcid":"0000-0001-9436-4857","position":11,"is_corresponding":false},{"id":35372,"name":"Francisco J. Sánchez‐Rivera","orcid":"0000-0002-8466-8563","position":12,"is_corresponding":false},{"id":16049,"name":"Kevin Meli","orcid":"0000-0002-9579-3829","position":13,"is_corresponding":false},{"id":39877,"name":"Manav Gupta","orcid":"0000-0001-5163-2911","position":14,"is_corresponding":false},{"id":39878,"name":"Roderick T. Bronson","orcid":"0000-0003-3725-2511","position":15,"is_corresponding":false},{"id":39879,"name":"Gregory J. Riely","orcid":"0000-0001-5357-4313","position":16,"is_corresponding":false},{"id":15544,"name":"Natasha Rekhtman","orcid":"0000-0001-5801-3144","position":17,"is_corresponding":false},{"id":1555,"name":"Charles M. Rudin","orcid":"0000-0001-5204-3465","position":18,"is_corresponding":false},{"id":28706,"name":"Carla F. Kim","orcid":"0000-0002-2366-9538","position":19,"is_corresponding":false},{"id":29633,"name":"Prisca Liberali","orcid":"0000-0003-0695-6081","position":20,"is_corresponding":false},{"id":3630,"name":"Jason D. Buenrostro","orcid":"0000-0001-9958-3987","position":21,"is_corresponding":false},{"id":14823,"name":"Tyler Jacks","orcid":"0000-0001-5785-8911","position":22,"is_corresponding":false},{"id":39872,"name":"Carla P. Concepcion","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}