SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing.

IF 29.5 1区 医学 Q1 HEMATOLOGY
Esther Redin, Harsha Sridhar, Yingqian A Zhan, Barbara Pereira Mello, Hong Zhong, Vidushi Durani, Amin Sabet, Parvathy Manoj, Irina Linkov, Juan Qiu, Richard P Koche, Elisa de Stanchina, Maider Astorkia, Doron Betel, Álvaro Quintanal-Villalonga, Charles M Rudin
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引用次数: 0

Abstract

Introduction: 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.

Methods: ATACseq and RNAseq experiments were performed in SCLC cells after pharmacological inhibition of SMARCA4. DNA binding of SMARCA4 was characterized by ChIPseq in high-NE SCLC patient derived xenografts (PDXs). Enrichment analyses were applied to transcriptomic data. Combination of FHD-286 and afatinib was tested in vitro and in a set of chemo-resistant SCLC PDXs in vivo.

Results: SMARCA4 expression positively correlates with that of NE genes in both SCLC cell lines and patient tumors. Pharmacological inhibition of SMARCA4 with FHD-286 induces the loss of NE features and downregulates neuroendocrine and neuronal signaling pathways while activating non-NE factors. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, enhancing NE programs. Enrichment analysis applied to high-confidence SMARCA4 targets confirmed neuron related pathways as the top GO Biological processes regulated by SMARCA4 in SCLC. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST transcript splicing. Furthermore, SMARCA4 inhibition drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib.

Conclusions: This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.

SMARCA4通过调节神经内分泌转录因子和REST剪接控制小细胞肺癌的状态可塑性。
简介:小细胞肺癌(SCLC小细胞肺癌(SCLC)可分为神经内分泌(NE)分化程度不同的转录亚型。最近的证据支持亚型之间的可塑性,即在疾病进展过程中或获得性化疗耐药时偏向于采用低NE状态。在这里,我们确定了SMARCA4(SWI/SNF复合物的催化亚基)在SCLC亚型转移中的调控作用:方法:药理抑制SMARCA4后,在SCLC细胞中进行ATACseq和RNAseq实验。在高NE SCLC患者衍生异种移植物(PDXs)中通过ChIPseq鉴定了SMARCA4的DNA结合。对转录组数据进行了富集分析。体外测试了FHD-286和阿法替尼的组合,体内测试了一组化疗耐药SCLC PDXs:结果:在SCLC细胞系和患者肿瘤中,SMARCA4的表达与NE基因的表达呈正相关。结果:SMARCA4的表达与SCLC细胞系和患者肿瘤中NE基因的表达呈正相关。用FHD-286对SMARCA4进行药理抑制可诱导NE特征的丧失,并下调神经内分泌和神经元信号通路,同时激活非NE因子。SMARCA4与编码NE系转录因子ASCL1和NEUROD1的基因位点结合,并改变染色质的可及性,从而增强NE程序。应用于高置信度 SMARCA4 靶点的富集分析证实,神经元相关通路是 SCLC 中受 SMARCA4 调控的顶级 GO 生物过程。与此同时,SMARCA4 还通过调节 SRRM4 依赖性 REST 转录本剪接来控制 REST,REST 是 NE 表型的已知抑制因子。此外,SMARCA4抑制还能驱动SCLC中ERBB通路的激活,使SCLC肿瘤对阿法替尼敏感:本研究认为SMARCA4是NE状态可塑性的关键调控因子,并为SCLC定义了一种新的治疗策略。
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来源期刊
CiteScore
48.10
自引率
2.10%
发文量
169
审稿时长
6-12 weeks
期刊介绍: The Journal of Hematology & Oncology, an open-access journal, publishes high-quality research covering all aspects of hematology and oncology, including reviews and research highlights on "hot topics" by leading experts. Given the close relationship and rapid evolution of hematology and oncology, the journal aims to meet the demand for a dedicated platform for publishing discoveries from both fields. It serves as an international platform for sharing laboratory and clinical findings among laboratory scientists, physician scientists, hematologists, and oncologists in an open-access format. With a rapid turnaround time from submission to publication, the journal facilitates real-time sharing of knowledge and new successes.
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