FOXL2 in Adult Granulosa Cell Tumorigenesis

项目摘要 成人颗粒细胞瘤（aGCT）约占20例卵巢癌中的1例，由卵巢上皮细胞形成。 活跃的卵泡驻留细胞负责排卵。AGCT通过减瘤手术治疗， 盆腔放射的可能性。没有标准的全身化疗。复发经常出现在 诊断后十年，治疗由主治肿瘤学家决定。FOXL2是一个 叉头转录因子家族的进化保守成员，是性腺发育所必需的。 发展FOXL2基因中超过100个妥协突变促进卵巢功能障碍， 颅面发育不良与此形成鲜明对比的是，一个单一的体细胞突变，FOXL2C134W，发生在近 在不同种族的400多名患者中进行了检查。我们表明，这 FOXL2基因是唯一存在于颗粒细胞瘤中的基因，具有活性和效力。然而，分子 FOXL2C134W致癌作用的基础尚不清楚， 体内突变在绝经期或刚过绝经期时出现aGCT的患者，提示初始情况 促进肿瘤的发展他们通常用手术和同样的化疗来治疗 提供给其他无关类型的卵巢癌。患有晚期疾病或复发的患者， 做得不好。增加对aGCT的了解可能为这些女性的治疗提供见解。这 由两位研究卵巢内分泌功能的合作PI提交的提案（岛崎） 和肿瘤形成和进展（Stupack），包括两个互补的目的，以了解的作用， FOXL2C134W在肿瘤发生中的作用。目的1：研究FOXL2C134W和FOXL2C130W在体外原位表达的效果 (the小鼠等效物）对完整和可接近的卵泡内GC功能的影响 类器官培养在目标2中，我们将通过以下方法直接测试FOXL2C134W表达对于肿瘤发生的充分性： 该基因的表达选择性GC在成年阶段的活小鼠。如果是这样，这将是第一个模型， 直接证明这种突变的因果关系，并应提供新的干预机会。

PROJECT SUMMARY Adult Granulosa Cell Tumors (aGCTs) account for about 1 in 20 ovarian cancers, forming from the hormonally active follicle resident cells responsible for ovulation. AGCTs are treated with debulking surgery, with the possibility of pelvic radiation. There is no standard systemic chemotherapy. Recurrence frequently comes a decade after diagnosis, with treatment left to the discretion of the attending oncologist. FOXL2 is an evolutionarily conserved member of the forkhead transcription factor family and is essential for gonadal development. More than 100 compromising mutations in the FOXL2 gene promote ovarian dysfunction and craniofacial misdevelopment. In striking contrast, a single somatic mutation, FOXL2C134W, occurs nearly universally in aGCTs, as examined across more than 400 patients of various ethnicities. We show that this FOXL2 gene, which is uniquely found in granulosa cell tumors, is active and potent. However, the molecular basis underlying the oncogenic effect of FOXL2C134W remains unclear, and nothing is known about the role of the mutation in vivo. Patients present with aGCTs at or just past menopause, suggesting an initiating circumstance that fosters tumor development. They are commonly treated with surgery and with the same chemotherapy offered to other unrelated types of ovarian cancer. Patients who present with advanced disease, or who recur, do poorly. An increased understanding of aGCT may provide insights for the treatment of these women. This proposal, submitted by two collaborating PIs who are experts in studying ovarian endocrine function (Shimasaki) and tumor formation and progression (Stupack), consists of two complementary aims to understand the role of FOXL2C134W in tumorigenesis. Aim 1 will evaluate the effects of in situ expression of FOXL2C134W or FOXL2C130W (the mouse equivalent) on GC function within intact and accessible follicles ex vivo using isolated mouse follicle organoid cultures. In Aim 2, we will directly test the sufficiency of FOXL2C134W expression for tumorigenesis, via expression of this gene selectively GCs at an adult stage of live mice. If so, this would be the first model to directly prove causality of this mutation and should offer new opportunities for intervention.