Dissecting the Pathogenesis of Ewing Sarcoma with Integrative Genomics

项目总结 尤文肉瘤是一种罕见的肿瘤，发生在儿童和年轻人中。而尤因肉瘤相对来说 罕见的是，这种疾病的生物学也与非尤文肉瘤和其他癌症亚型有关，原因是 EWS/FLI易位的存在是该病的驱动事件。类似的易位涉及 ETS转录因子在其他恶性肿瘤中也存在，包括前列腺癌。因此，理解 尤文肉瘤的生物学可以提供对许多癌症类型的洞察。我们将调查 尤文肉瘤发病机制中的继发性遗传事件。这些次要事件一直是 通过对原发肿瘤和细胞系的下一代测序进行鉴定。具体地说，我们将评估 STAG2在介导癌基因驱动引起的表观遗传和转录变化中的作用 尤因肉瘤，EWS/FLI。 在目标1中，我们将使用基因组方法(RNAseq、ChIPseq、WGS等)。评估…的机械性作用 STAG2在尤文细胞染色质结构、转录和非整倍体调控中的作用。在目标2中，我们 将研究STAG2在尤文肉瘤的进展、维持和转移中的作用，使用功能性 尤文肉瘤细胞系和患者来源的异种移植的研究。在目标3中，我们将确定是否存在 当尤文肉瘤细胞中没有STAG2时，对STAG1的合成致死依赖。我们的中央 假设STAG2缺失在驱动致癌的表观遗传重编程中起关键作用 EWS/FLI功能。

PROJECT SUMMARY Ewing sarcoma is a rare tumor that occurs in children and young adults. While Ewing sarcoma is relatively rare, the biology of this disease is also relevant to non-Ewing sarcomas, and to other cancer subtypes, due to the presence of the EWS/FLI translocation, the driving event in this disease. Similar translocations involving ETS transcription factors occur in other malignancies, including prostate cancer. Thus, understanding the biology of Ewing sarcoma may provide insight into many cancer types. We will investigate the role of secondary genetic events in the pathogenesis of Ewing sarcoma. These secondary events have been identified through next-generation sequencing of primary tumors and cell lines. Specifically, we will evaluate the role of STAG2 in mediating epigenetic and transcriptional changes induced by the driving oncogene in Ewing sarcoma, EWS/FLI. In Aim 1, we will use genomic approaches (RNAseq, ChIPseq, WGS, etc.) to assess the mechanistic role of STAG2 in the regulation of chromatin architecture, transcription, and aneuploidy in Ewing cells. In Aim 2, we will study the role of STAG2 in progression, maintenance and metastasis in Ewing sarcoma, using functional studies in Ewing sarcoma cell lines and patient-derived xenografts. In Aim 3, we will determine whether there is a synthetic lethal dependency on STAG1 when STAG2 is absent in Ewing sarcoma cells. Our central hypothesis is that STAG2 loss plays a key role in the epigenetic reprogramming that drives the oncogenic function of EWS/FLI.