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

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. Overall design: Single-cell ATAC-seq on isolated cancer cells from murine lung adenocarcinoma models of Smarca4 loss