Smarca4 Inactivation Promotes Lineage-Specific Transformation and Early Metastatic Features in the Lung

Concepcion, Carla P, Ma, Sai, LaFave, Lindsay M, Bhutkar, Arjun, Liu, Manyuan, DeAngelo, Lydia P, Kim, Jonathan Y, Del Priore, Isabella, Schoenfeld, Adam J, Miller, Manon, Kartha, Vinay K, Westcott, Peter MK, Sánchez-Rivera, Francisco J, Meli, Kevin, Gupta, Manav, Bronson, Roderick T, Riely, Gregory J, Rekhtman, Natasha, Rudin, Charles M, Kim, Carla F, Regev, Aviv, Buenrostro, Jason D, Jacks, Tyler (February 2022) Smarca4 Inactivation Promotes Lineage-Specific Transformation and Early Metastatic Features in the Lung. Cancer Discovery, 12 (2). pp. 562-585. ISSN 0008-5472

Abstract

SMARCA4/BRG1 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 SMARCA4 mutation on tumor initiation, progression, and chromatin regulation in lung cancer remain poorly understood. Here, we demonstrate that loss of Smarca4 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, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and resemble a metastatic cell state. Mechanistically, we show that Smarca4 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 Smarca4 acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution. SIGNIFICANCE: 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.This article is highlighted in the In This Issue feature, p. 275.

Item Type: Paper
Subjects: bioinformatics
diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organism description > animal
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell transformation
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > helicase
diseases & disorders > cancer > cancer types > lung cancer
organism description > animal > mammal
diseases & disorders > cancer > metastasis
organism description > animal > mammal > rodent > mouse
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organism description > animal > mammal > rodent
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Westcott lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: February 2022
Date Deposited: 27 Jul 2022 16:52
Last Modified: 11 Jan 2024 19:27
PMCID: PMC8831463
URI: https://repository.cshl.edu/id/eprint/40691

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