Adult type ovarian granulosa cell tumors (AGCTs) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a Forkhead box-family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2-C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2-C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific chromatin remodeling activity in FOXL2. FOXL2-C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduced viability, and dexamethasone rescued this effect. Combinatorial drug-drug interaction experiments demonstrated that dexamethasone antagonizes the potency of paclitaxel, a chemotherapy agent frequently used in the treatment of AGCT. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2-C134W and creates a potentially targetable synergy with glucocorticoid signaling.

中文翻译：

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致癌 FOXL2-C134W 的功能获得性染色质重塑活性重编程糖皮质激素受体占有率以驱动颗粒细胞瘤


成人型卵巢颗粒细胞瘤 （AGCT） 是一种罕见的恶性肿瘤，在 FOXL2 中具有几乎普遍的 c.C402G （p.Cys134Trp） 体细胞突变，FOXL2 是一种对卵巢功能很重要的叉头盒家族转录因子。复发性 AGCT 无法治愈，但独特的 FOXL2 突变机制可能会赋予治疗脆弱性。为了确定 FOXL2-C134W 依赖性药理协同作用，我们创建并表征了内源性 FOXL2 同基因 AGCT 细胞和 AGCT 类瘤生物库。药物筛选发现糖皮质激素促进 FOXL2-C134W 依赖性 AGCT 生长。表观遗传学调查显示，Cys134Trp 突变暴露了 FOXL2 中潜在的 DNA 序列特异性染色质重塑活性。FOXL2-C134W 依赖性染色质重塑活性重定向糖皮质激素受体染色质占有率，以驱动透明质酸合酶 2 基因表达并增加细胞外透明质酸分泌。用透明质酸酶处理 AGCT 模型降低了活力，而地塞米松挽救了这种效果。组合药物相互作用实验表明，地塞米松拮抗紫杉醇的效力，紫杉醇是一种经常用于治疗 AGCT 的化疗药物。因此，功能获得性开拓活性有助于 FOXL2-C134W 的致癌机制，并与糖皮质激素信号传导产生潜在的靶向协同作用。