SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>SMARCA4/BRG1 encodes for one of two mutually exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes and is frequently mutated...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Association for Cancer Research (AACR)
2022
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| Online Access: | https://hdl.handle.net/1721.1/146824 |
| _version_ | 1811076976928096256 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 |
| author_sort | Concepcion, Carla P |
| collection | MIT |
| description | <jats:title>Abstract</jats:title>
<jats:sec>
<jats:title />
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Significance:</jats:title>
<jats: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.</jats:p>
<jats:p>This article is highlighted in the In This Issue feature, p. 275</jats:p>
</jats:sec> |
| first_indexed | 2024-09-23T10:33:17Z |
| format | Article |
| id | mit-1721.1/146824 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:33:17Z |
| publishDate | 2022 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1468242022-12-10T03:33:32Z 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 Massachusetts Institute of Technology. Department of Biology <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats: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.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 275</jats:p> </jats:sec> 2022-12-09T19:05:19Z 2022-12-09T19:05:19Z 2022 2022-12-09T18:57:56Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146824 Concepcion, Carla P, Ma, Sai, LaFave, Lindsay M, Bhutkar, Arjun, Liu, Manyuan et al. 2022. "SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung." Cancer Discovery, 12 (2). en 10.1158/2159-8290.CD-21-0248 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | 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 SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung |
| title | SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung |
| title_full | SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung |
| title_fullStr | SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung |
| title_full_unstemmed | SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung |
| title_short | SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung |
| title_sort | smarca4 inactivation promotes lineage specific transformation and early metastatic features in the lung |
| url | https://hdl.handle.net/1721.1/146824 |
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