Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft-tissue malignancy with a poor overall survival and no effective therapeutic options. The tumor is believed to be dependent on the continued activity of the oncogenic EWS-WT1 transcription factor. However, the dependence of the tumor on EWS-WT1 has not been well established. In addition, there are no studies exploring the downstream transcriptional program across multiple cell lines. In this study, we have developed a novel approach to selectively silence EWS-WT1 without impacting either wild-type EWSR1 or WT1. We show a clear dependence of the tumor on EWS-WT1 in two different cell lines, BER and JN-DSCRT-1. In addition, we identify and validate important downstream target pathways commonly dysregulated in other translocation-positive sarcomas, including PRC2, mTOR, and TGFB. Surprisingly, there is striking overlap between the EWS-WT1 and EWS-FLI1 gene signatures, despite the fact that the DNA-binding domain of the fusion proteins, WT1 and FLI1, is structurally unique and classified as different types of transcription factors. This study provides important insight into the biology of this disease relative to other translocation-positive sarcomas, and the basis for the therapeutic targeting of EWS-WT1 for this disease that has limited therapeutic options.

中文翻译：

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增生性小圆形细胞肿瘤取决于EWS-WT1转录因子。

增塑小圆形细胞瘤（DSRCT）是一种罕见的侵袭性软组织恶性肿瘤，总体生存率低，没有有效的治疗选择。据信肿瘤取决于致癌的EWS-WT1转录因子的持续活性。然而，尚未完全确定肿瘤对EWS-WT1的依赖性。另外，还没有研究探索跨多个细胞系的下游转录程序。在这项研究中，我们已经开发出一种新颖的方法，可以选择性地使EWS-WT1沉默而不影响野生型EWSR1或WT1。我们在两个不同的细胞系BER和JN-DSCRT-1中显示出对EWS-WT1肿瘤的明确依赖性。此外，我们确定并验证了在其他易位阳性肉瘤（包括PRC2，mTOR和TGFB）中通常失调的重要下游靶途径。出乎意料的是，尽管融合蛋白WT1和FLI1的DNA结合结构域在结构上是独特的，并被归类为不同类型的转录因子，但EWS-WT1和EWS-FLI1基因签名之间却出现了惊人的重叠。这项研究为该疾病相对于其他易位阳性肉瘤的生物学提供了重要的见识，并为该疾病的治疗选择提供了针对EWS-WT1的治疗靶向基础。