Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.

中文翻译：

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WDR5 代表胶质母细胞瘤中癌症干细胞的治疗可利用靶点


胶质母细胞瘤 (GBM) 是一种由癌症干细胞 (CSC) 群体驱动的异质性、难治性肿瘤。然而，很少有对 CSC 群体维持至关重要的分子机制被用于治疗开发。我们在 GBM 患者来源的类器官中开发了一种空间分辨的功能丧失筛查，以识别富含 SOX2 的治疗抵抗生态位中的重要表观遗传调节因子，并确定 WDR5 对于该人群是不可或缺的。 WDR5 是 WRAD 复合体的一个组成部分，可促进 SET1 家族介导的组蛋白 H3 (H3K4me) Lys4 甲基化，与转录的正向调节相关。在 GBM CSC 中，WDR5 抑制剂阻断 WRAD 复合物组装，并减少 H3K4 三甲基化和参与 CSC 相关致癌途径的基因表达。 WDR5 抑制剂处理后 H3K4me3 峰丢失不成比例地发生在 POU 转录因子基序上，包括 POU5F1(OCT4)::SOX2 基序。 SOX2/OCT4 报告基因的使用表明，WDR5 抑制剂处理减少了具有高报告基因活性的细胞。此外，WDR5 抑制剂治疗和 WDR5 敲除改变了干细胞状态，破坏了 CSC 的体外生长和自我更新，以及体内肿瘤的生长。这些发现强调了 WDR5 和 WRAD 复合物在维持 CSC 状态中的作用，并为 GBM 和其他晚期癌症的 WDR5 抑制剂的治疗开发提供了理论基础。