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The MYC-SWI/SNF connection in rhabdoid tumors

横纹肌样瘤中的 MYC-SWI/SNF 连接

基本信息

批准号：
10624309
负责人：
William Patrick Tansey
金额：
$ 36.42万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624309
关键词：
Acute Automobile Driving Binding Biochemical Biological Assay Cell Survival Cells Child Chromatin Chromatin Remodeling Factor Complex DNA DNA Binding Data Dependence Diagnosis Disease Elements Etiology Event Exposure to Gene Expression Profile Genes Genetic Genetic Transcription Genome Genomic approach Genomics Goals Link Location Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Modeling Molecular Mutate Mutation Nature Normal Cell Oncogenic Oncoproteins Operative Surgical Procedures Pathway interactions Patients Pattern Process Productivity Radiation Recurrence Residual state Resolution Rhabdoid Tumor Role SMARCB1 gene SMARCC1 gene SWI/SNF Family Complex Shapes Site Techniques Therapeutic Therapeutic Intervention Transcription Process Treatment Protocols Tumor Suppressor Proteins Variant Work c-myc Genes cell transformation chemotherapy experience genetic approach genetic signature inhibitor innovation mortality neoplastic cell novel pharmacologic predictive modeling prevent programs protein complex rare cancer recruit restraint targeted treatment therapeutically effective transcription factor transcriptome transcriptomics tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY Rhabdoid tumors are rare and aggressive pediatric cancers with high rates of mortality and few treatment options. Most children diagnosed with rhabdoid tumors will die within 18 months of diagnosis, often after grueling treatment regimens that involve combinations of surgery, chemotherapy, and radiation. The molecular basis of rhabdoid tumors is remarkably simple, and involves loss of a single tumor suppressor— SMARCB1—which encodes the SNF5 component of the SWI/SNF chromatin remodeler. Identification of SNF5 loss as the driver of rhabdoid tumors was a major breakthrough in understanding the disease, but raises the question of how the absence of SNF5 promotes tumorigenic programs and whether there are actionable targets for therapeutic intervention in these cancers. The premise of this project is that loss of SNF5 causes rhabdoid tumors, at least in part, by activating c-MYC, an oncoprotein transcription factor with extensive ties to cancer. Supporting this premise are preliminary data showing: (i) an extensive overlap between the primary transcriptional effects of MYC inhibition and SNF5 re-introduction in rhabdoid tumor cells, (ii) physical interactions between MYC and SWI/SNF components that are blocked by SNF5, (iii) the ability of SNF5 to separately inhibit DNA binding by MYC, (iv) MYC-dependent recruitment of a core SWI/ SNF component to chromatin in rhabdoid tumor cells, and (v) an essential role for MYC in rhabdoid tumor cell survival and transformation. Together, these data explain the recurrent presence of MYC target gene signatures in rhabdoid tumor patients, and support a model in which loss of SNF5 stimulates a productive interaction of MYC on chromatin with 'residual' SWI/SNF complexes—which in turn drives key tumorigenic transcriptional programs in these malignancies. The goal of this project is to characterize the MYC–SWI/ SNF connection in rhabdoid tumor cells, and determine its role in sculpting the rhabdoid transcriptome. Specific Aim 1 will use a combination of biochemical, genetic, and genomic approaches to define components of the MYC–SWI/SNF complex and to characterize their recruitment to sites across the rhabdoid genome. Specific Aim 2 will combine high resolution transcriptomic analyses with cell-based assays to reveal primary transcriptional events that are controlled via the MYC–SWI/SNF interaction in rhabdoid tumor cells and to decipher the underlying mechanisms. Completion of these studies will rigorously challenge the idea that MYC is a defacto driver of oncogenic transcriptional processes in these cancers. These studies will also expose whether MYC inhibitors are likely to be an effective therapeutic option in rhabdoid cancers, and will establish a paradigm for how tumor-associated mutations in SWI/SNF— which occur in 20% of all cancers—intersect with classic oncogenic pathways to drive malignancy.

项目摘要横纹肌样瘤是一种罕见的侵袭性儿科癌症，死亡率高，治疗很少选项.大多数被诊断患有横纹肌样瘤的儿童将在诊断后18个月内死亡，通常在包括手术、化疗和放疗在内的艰苦的治疗方案。的横纹肌样瘤的分子基础非常简单，包括单个肿瘤抑制因子的丢失， SMARCB 1-编码SWI/SNF染色质重塑物的SNF 5组分。鉴定 SNF 5缺失作为横纹肌样肿瘤的驱动因素是理解这种疾病的一个重大突破，提出了SNF 5的缺失如何促进肿瘤发生程序以及是否存在这些癌症的治疗干预的可行目标。这个项目的前提是， SNF 5至少部分通过激活c-MYC（一种癌蛋白转录因子，与癌症有着广泛的联系支持这一假设的初步数据显示：横纹肌样瘤中MYC抑制和SNF 5重新引入的初级转录效应之间的关系细胞，（ii）被SNF 5阻断的MYC和SWI/SNF组分之间的物理相互作用，（iii） SNF 5单独抑制MYC与DNA结合的能力，（iv）MYC依赖性募集核心SWI， SNF组分在横纹肌样肿瘤细胞中的染色质，以及（v）MYC在横纹肌样肿瘤中的重要作用细胞存活和转化。总之，这些数据解释了MYC靶基因的反复存在。在横纹肌样肿瘤患者中的信号，并支持一种模型，在该模型中SNF 5的缺失刺激了生产性的染色质上MYC与“残留”SWI/SNF复合物的相互作用--这反过来又驱动了关键的致瘤性这些恶性肿瘤中的转录程序。本项目的目标是描述MYC-SWI/ SNF在横纹肌样肿瘤细胞中的连接，并确定其在塑造横纹肌样转录组中的作用。具体目标1将使用生物化学，遗传学和基因组方法的组合来定义 MYC-SWI/SNF复合物的组成部分，并描述其在整个研究中心的招募情况。横纹肌样基因组。Specific Aim 2将联合收割机高分辨率转录组学分析与基于细胞的揭示通过MYC-SWI/SNF相互作用控制的初级转录事件的分析，横纹肌样肿瘤细胞和破译潜在的机制。完成这些研究将严格挑战的想法，MYC是一个事实上的驱动程序致癌转录过程中，这些癌的这些研究还将揭示MYC抑制剂是否可能是一种有效的治疗方法在横纹肌样癌的选择，并将建立一个范例，如何在SWI/SNF肿瘤相关突变- 发生在20%的癌症中，与经典的致癌途径交叉，导致恶性肿瘤。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Emerging Themes in Mechanisms of Tumorigenesis by SWI/SNF Subunit Mutation.

DOI：
10.1177/25168657221115656
发表时间：
2022
期刊：
EPIGENETICS INSIGHTS
影响因子：
2.2
作者：
Jones, Cheyenne A.;Tansey, William P.;Weissmiller, April M.
通讯作者：
Weissmiller, April M.

The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells.

SWI/SNF ATPase BRG1 促进 SMARCB1 缺陷癌细胞中的多种促肿瘤基因表达程序。

DOI：
10.1038/s41389-022-00406-6
发表时间：
2022-06-01
期刊：
ONCOGENESIS
影响因子：
6.2
作者：
Moe, Kylie C.;Maxwell, Jack N.;Wang, Jing;Jones, Cheyenne A.;Csaki, Grace T.;Florian, Andrea C.;Romer, Alexander S.;Bryant, Daniel L.;Farone, Anthony L.;Liu, Qi;Tansey, William P.;Weissmiller, April M.
通讯作者：
Weissmiller, April M.