The MYC-SWI/SNF connection in rhabdoid tumors

项目总结 横纹肌样瘤是一种少见的侵袭性儿科癌症，死亡率高，治疗很少。 选择。大多数被诊断患有横纹肌肉瘤的儿童会在确诊后18个月内死亡，通常是在 令人精疲力竭的治疗方案，包括手术、化疗和放射治疗的组合。这个 横纹肌样肿瘤的分子基础非常简单，只涉及一种肿瘤抑制因子的缺失- SMARCB1-编码SWI/SNF染色质重构器的SNF5组件。身份识别 SNF5作为横纹肌样肿瘤的驱动因素的缺失是对这种疾病认识的一个重大突破，但 提出了这样一个问题：SNF5的缺失如何促进致癌计划，以及是否存在 这些癌症治疗干预的可操作靶点。这个项目的前提是损失 SNF5导致横纹肌样肿瘤，至少部分是通过激活c-myc，一种癌蛋白转录因子 与癌症有着广泛的联系。支持这一前提的是初步数据显示：(I)广泛的重叠 横纹肌样瘤中MYC抑制和SNF5重新导入对转录的影响 细胞，(Ii)被SNF5阻断的MYC和SWI/SNF组件之间的物理相互作用，(Iii) SNF5单独抑制MYC结合DNA的能力，(Iv)依赖MYC的核心SWI/ 横纹肌样瘤细胞中SNF组分对染色质的作用，以及(V)MYC在横纹肌样瘤中的重要作用 细胞的存活和转化。总之，这些数据解释了MYC靶基因的反复存在。 横纹肌样肿瘤患者的特征，并支持SNF5缺失刺激生产力的模型 染色质上MYC与残存的SWI/SNF复合体的相互作用--进而驱动关键的致癌作用 这些恶性肿瘤中的转录程序。该项目的目标是描述MYC-SWI/ SNF在横纹肌样肿瘤细胞中的连接，并确定其在横纹肌样转录组的雕刻中的作用。 特定目标1将使用生化、遗传和基因组方法的组合来定义 MYC-SWI/SNF复合体的组成部分，并描述他们在全国各地的招募情况 横纹肌样基因组。特殊目标2将结合高分辨率转录分析和基于细胞的分析 揭示通过MYC-SWI/SNF相互作用控制的主要转录事件的分析 横纹肌样肿瘤细胞并破译其潜在机制。完成这些研究后， 严格挑战MYC是这些肿瘤中致癌转录过程的事实上驱动因素的观点 癌症。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 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- 发生在所有癌症中的20%-与经典的致癌途径相交，从而导致恶性肿瘤。

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.