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| Status |
Public on Aug 28, 2024 |
| Title |
SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Small Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, suppressing NE programs. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST splicing. The SMARCA2/4 inhibitor FHD-286 induces loss of NE features and drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib. This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.
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| Overall design |
To study the role of SMARCA4/2 in regulating the neuroendocrine phenotype in SCLC, we pharmacologically inhibited this target using FHD-286 and performed gene expression profiling analysis by RNAseq. We treated H146 and H82 cells for 14 days with 100nM of FHD-286. Comparative gene expression profiling of RNAseq data for H82 and H146 treated vs untreated cells.
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| Contributor(s) |
Redin E, Zhan YA, Rudin CM |
| Citation(s) |
39080761 |
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| Submission date |
Feb 22, 2024 |
| Last update date |
Aug 28, 2024 |
| Contact name |
Yingqian Ada Zhan |
| E-mail(s) |
zhany@mskcc.org
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| Organization name |
MSKCC
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| Department |
EPIGENETICS RESEARCH CENTER
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| Street address |
430 East 67th Street
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| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (13)
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| GSM8094137 |
H146 cells, treated n1 (RNA-seq) |
| GSM8094138 |
H146 cells, treated n2 (RNA-seq) |
| GSM8094139 |
H146 cells, treated n3 (RNA-seq) |
| GSM8094140 |
H146 cells, treated n4 (RNA-seq) |
| GSM8094141 |
H82 cells, untreated n1 (RNA-seq) |
| GSM8094142 |
H82 cells, untreated n2 (RNA-seq) |
| GSM8094143 |
H82 cells, untreated n3 (RNA-seq) |
| GSM8094144 |
H82 cells, treated n1 (RNA-seq) |
| GSM8094145 |
H82 cells, treated n2 (RNA-seq) |
| GSM8094146 |
H82 cells, treated n3 (RNA-seq) |
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| Relations |
| BioProject |
PRJNA1079237 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE256347_DESeq2_RNAseq_hg38_TPMs_H146.txt.gz |
1.4 Mb |
(ftp)(http) |
TXT |
| GSE256347_DESeq2_RNAseq_hg38_TPMs_H82.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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