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>