Comprehensive Analysis of SWI/SNF Inactivation in Lung Adenocarcinoma Cell Models

Peinado, Paola; Andrades, Álvaro; Cuadros, Marta; Rodríguez, María I.; Coira, Isabel F.; García, Daniel Jesús García; Álvarez-Pérez, Juan Carlos; Baliñas-Gavira, Carlos; Arenas, Alberto Muñoz; Patiño-Mercau, Juan Rodrigo; Sanjuan-Hidalgo, Juan; Romero, Octavio A.; Montuenga, Luis M.; Carretero, Julián; Sánchez-Céspedes, Montserrat; Medina, Pedro P.

doi:10.3390/cancers12123712

Cited by 6 publications

(8 citation statements)

References 43 publications

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“…NGS studies have identified that the multiprotein complex SWI/SNF ( SWitch/Sucrose Non-Fermentable ) is mutated in almost 25% of human neoplasias [ 2 , 3 ]. Before the era of NGS, our group discovered that SMARCA4 is frequently inactivated by truncating mutations in LUAD [ 4 – 6 ]. Together with SMARCA4 , other SWI/SNF subunits, such as ARID1A , are recurrently mutated in LUAD and considered as LUAD driver genes [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Together with SMARCA4 , other SWI/SNF subunits, such as ARID1A , are recurrently mutated in LUAD and considered as LUAD driver genes [ 7 ]. Recently, our group has shown that more than 76% of LUAD cell lines have at least one mutated SWI/SNF subunit [ 6 ]. However, the exact composition of the SWI/SNF complex in LUAD is currently unknown and we lack an integration of the genetic and transcriptional profile of this complex in order to facilitate a practical transfer to the clinic.…”

Section: Introductionmentioning

confidence: 99%

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Multi-omic alterations of the SWI/SNF complex define a clinical subgroup in lung adenocarcinoma

et al. 2022

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SWI/SNF complexes are major targets of mutations in cancer. Here, we combined multiple “-omics” methods to assess SWI/SNF composition and aberrations in LUAD. Mutations in lung SWI/SNF subunits were highly recurrent in our LUAD cohort (41.4%), and over 70% of the mutations were predicted to have functional impact. Furthermore, SWI/SNF expression in LUAD suffered an overall repression that could not be explained exclusively by genetic alterations. Finally, SWI/SNF mutations were associated with poorer overall survival in TCGA-LUAD. We propose SWI/SNF-mutant LUAD as a separate clinical subgroup with practical implications.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multi-omic alterations of the SWI/SNF complex define a clinical subgroup in lung adenocarcinoma

et al. 2022

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“…SMARCA4 and SMARCA2 loss are the main immunohistochemical markers of SMARCA4‐dUT, although some SMARCA4‐deficient NSCLC tumors can also present these same features [5]. In our previous study of the SWI/SNF expression and mutational status on a panel of 38 LUAD cell lines, we discovered that three cell lines harbored SMARCA4 inactivating mutations, and they had a null expression of SMARCA2 : A427, NCI‐H23, and NCI‐H522 [7].…”

Section: Resultsmentioning

confidence: 99%

“…We recently characterized the mutational status and expression profile of 20 SWI/SNF members in 38 LUAD cell lines and tumor patient samples [7,8]. Because SMARCA4-dUT was just recently included in the 2021 WHO classification of lung tumors, there is a possibility that some of the cell lines previously classified as LUAD cell lines could now be better reinterpreted as SMARCA4-dUT.…”

Section: Introductionmentioning

confidence: 99%

Defining the first bona fide cell model for SMARCA4‐deficient, undifferentiated tumor

Arenas,

Ruiz‐Jiménez,

López‐Hidalgo

et al. 2023

The Journal of Pathology

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The World Health Organization's tumor classification guidelines are frequently updated and renewed as knowledge of cancer biology advances. For instance, in 2021, a novel lung tumor subtype named SMARCA4‐deficient, undifferentiated tumor (SMARCA4‐dUT, code 8044/3) was included. To date, there is no defined cell model for SMARCA4‐dUT that could be used to help thoracic clinicians and researchers in the study of this newly defined tumor type. As this tumor type was recently described, it is feasible that some cell models formerly classified as lung adenocarcinoma (LUAD) could now be better classified as SMARCA4‐dUT. Thus, in this work, we aimed to identify a bona fide cell model for the experimental study of SMARCA4‐dUT. We compared the differential expression profiles of 36 LUAD‐annotated cell lines and 38 cell lines defined as rhabdoid in repositories. These comparative results were integrated with the mutation and expression profiles of the SWI/SNF complex members, and they were surveyed for the presence of the SMARCA4‐dUT markers SOX2, SALL4, and CD34, measured by RT‐qPCR and western blotting. Finally, the cell line with the paradigmatic SMARCA4‐dUT markers was engrafted into immunocompromised mice to assess the histological morphology of the formed tumors and compare them with those formed by a bona fide LUAD cancer cell line. NCI‐H522, formerly classified as LUAD, displayed expression profiles nearer to rhabdoid tumors than LUAD tumors. Furthermore, NCI‐H522 has most of the paradigmatic features of SMARCA4‐dUT: hemizygous inactivating mutation of SMARCA4, severe SMARCA2 downregulation, and high‐level expression of stem cell markers SOX2 and SALL4. In addition, the engrafted tumors of NCI‐H522 did not display a typical differentiated glandular structure as other bona fide LUAD cell lines (A549) do but had rather a largely undifferentiated morphology, characteristic of SMARCA4‐dUT. Thus, we propose the NCI‐H522 as the first bona fide cell line model of SMARCA4‐dUT. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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“…Massive sequencing studies have revealed that SWI/SNF complexes are among the most recurrently mutated functional elements across all tumor types, reaching an overall mutation rate of 25% [ 7 ]. Mutations found in cancer-related SWI/SNF subunits are mostly deleterious [ 8 ], consistent with the widespread tumor suppressor function of the complex. Accordingly, sequencing studies in AML have also found tumor suppressor-like mutation patterns in SWI/SNF genes [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 85%

BCL7A is silenced by hypermethylation to promote acute myeloid leukemia

et al. 2023

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Background Recent massive sequencing studies have revealed that SWI/SNF complexes are among the most frequently altered functional entities in solid tumors. However, the role of SWI/SNF in acute myeloid leukemia is poorly understood. To date, SWI/SNF complexes are thought to be oncogenic in AML or, at least, necessary to support leukemogenesis. However, mutation patterns in SWI/SNF genes in AML are consistent with a tumor suppressor role. Here, we study the SWI/SNF subunit BCL7A, which has been found to be recurrently mutated in lymphomas, but whose role in acute myeloid malignancies is currently unknown. Methods Data mining and bioinformatic approaches were used to study the mutational status of BCL7A and the correlation between BCL7A expression and promoter hypermethylation. Methylation-specific PCR, bisulfite sequencing, and 5-aza-2'-deoxycytidine treatment assays were used to determine if BCL7A expression was silenced due to promoter hypermethylation. Cell competition assays after BCL7A expression restoration were used to assess the role of BCL7A in AML cell line models. Differential expression analysis was performed to determine pathways and genes altered after BCL7A expression restoration. To establish the role of BCL7A in tumor development in vivo, tumor growth was compared between BCL7A-expressing and non-expressing mouse xenografts using in vivo fluorescence imaging. Results BCL7A expression was inversely correlated with promoter methylation in three external cohorts: TCGA-LAML (N = 160), TARGET-AML (N = 188), and Glass et al. (2017) (N = 111). The AML-derived cell line NB4 silenced the BCL7A expression via promoter hypermethylation. Ectopic BCL7A expression in AML cells decreased their competitive ability compared to control cells. Additionally, restoration of BCL7A expression reduced tumor growth in an NB4 mouse xenograft model. Also, differential expression analysis found that BCL7A restoration altered cell cycle pathways and modified significantly the expression of genes like HMGCS1, H1-0, and IRF7 which can help to explain its tumor suppressor role in AML. Conclusions BCL7A expression is silenced in AML by promoter methylation. In addition, restoration of BCL7A expression exerts tumor suppressor activity in AML cell lines and xenograft models.

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Comprehensive Analysis of SWI/SNF Inactivation in Lung Adenocarcinoma Cell Models

Cited by 6 publications

References 43 publications

Multi-omic alterations of the SWI/SNF complex define a clinical subgroup in lung adenocarcinoma

Multi-omic alterations of the SWI/SNF complex define a clinical subgroup in lung adenocarcinoma

Defining the first bona fide cell model for SMARCA4‐deficient, undifferentiated tumor

BCL7A is silenced by hypermethylation to promote acute myeloid leukemia

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