Welte Thomas, Vuttaradhi Veena K, Khlebus Eleonora Y, Brodsky Allison, Flores Legarreta Alejandra, Celestino Joseph, Powell Reid T, Stephan Clifford C, Nguyen Nghi, Li Jian, Takamatsu Shiro, Calzoncinth Katherine, Sood Anil K, Gershenson David M, Futreal P Andrew, Lawson Barrett, Hillman R Tyler
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Texas A&M Health Center for Translational Cancer Research, Houston, Texas.
Cancer Res. 2025 Mar 3;85(5):875-893. doi: 10.1158/0008-5472.CAN-24-2341.
Adult type ovarian granulosa cell tumors (AGCT) 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 FOXL2C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific chromatin remodeling activity in FOXL2. FOXL2C134W-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 FOXL2C134W and creates a potentially targetable synergy with glucocorticoid signaling. Significance: Glucocorticoids promote granulosa cell tumor growth via epigenetic coregulation with the disease driver FOXL2C134W, providing mechanistic insight into disease oncogenesis and uncovering a potential treatment strategy.
成人型卵巢颗粒细胞瘤（AGCT）是一种罕见的恶性肿瘤，在叉头框家族转录因子FOXL2中几乎普遍存在c.C402G（p.Cys134Trp）体细胞突变，该转录因子对卵巢功能很重要。复发性AGCT无法治愈，但独特的FOXL2突变机制可能导致治疗上的脆弱性。为了确定FOXL2C134W依赖性的药物协同作用，我们创建并表征了内源性FOXL2同基因AGCT细胞和一个AGCT类肿瘤生物样本库。药物筛选发现糖皮质激素可促进FOXL2C134W依赖性的AGCT生长。表观遗传学研究表明，Cys134Trp突变暴露了FOXL2中潜在的DNA序列特异性染色质重塑活性。FOXL2C134W依赖性染色质重塑活性将糖皮质激素受体的染色质占据重新定向，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模型可降低细胞活力，地塞米松可挽救这种效应。联合药物相互作用实验表明，地塞米松可拮抗紫杉醇（一种常用于治疗AGCT的化疗药物）的效力。因此，功能获得性的先锋活性促成了FOXL2C134W的致癌机制，并与糖皮质激素信号传导产生了潜在的可靶向协同作用。意义：糖皮质激素通过与疾病驱动因子FOXL2C134W的表观遗传共同调节来促进颗粒细胞瘤生长，为疾病的肿瘤发生提供了机制性见解，并揭示了一种潜在的治疗策略。
