FOXL2 in Adult Granulosa Cell Tumorigenesis

FOXL2 在成人颗粒细胞肿瘤发生中的作用

• 批准号: 10622537
• 负责人: SHUNICHI SHIMASAKI
• 金额: $ 35.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622537
• 关键词: 3-Dimensional; Activins; Adult; Aging; Aromatase; Aromatase Inhibitors; Bioinformatics; Biology; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Collaborations; Craniofacial Abnormalities; Dependence; Detection; Development; Diagnosis; Disease; Doxycycline; Endocrine; Endometrial; Environment; Enzymes; Estrogen Receptors; Estrogens; Ethnic Origin; Etiology; FOXO1A gene; Family; Female; Fostering; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Geographic Locations; Goals; Grant; Homeostasis; Hormonal; Human; In Situ; In Vitro; Infertility; Intervention; Left; Life; Ligands; MADH3 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Oncogenic; Oncologist; Oocytes; Operative Surgical Procedures; Organoids; Outcome; Ovarian; Ovarian Follicle; Ovarian Granulosa Cell; Ovary; Ovulation; Patients; Pelvis; Pharmaceutical Preparations; Physiological; Postmenopause; Radiation; Recommendation; Recurrence; Recurrent disease; Research Personnel; Role; Serum; Signal Transduction; Somatic Mutation; System; Telomerase; Testing; Time; Tissues; Transcript; Transgenic Mice; Transplantation; Tumor Debulking; Woman; advanced disease; autocrine; blepharophimosis-ptosis-epicanthus inversus syndrome; chemotherapy; clinical development; clinical diagnosis; craniofacial; craniofacial development; folliculogenesis; forkhead protein; gonad development; granulosa cell; granulosa cell tumor; in vivo; inducible gene expression; inhibitor; innovation; insight; member; mouse model; mutant; novel; ovarian dysfunction; paracrine; pharmacologic; preclinical development; prevent; prognostic; reproductive tract; sex; standard of care; theca cell; transcription factor; transcriptome; tumor; tumorigenesis

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.

项目总结 成人颗粒细胞瘤(AGCT)约占卵巢癌20例中的1例，由激素引起 活跃的卵泡驻留细胞负责排卵。AGCT接受整形手术治疗， 可能有骨盆辐射。没有标准的全身化疗。复发经常发生在 诊断十年后，治疗由主治肿瘤学家自行决定。FOXL2是一个 在进化上保守的叉头转录因子家族成员，对性腺来说是必不可少的 发展。FOXL2基因的100多个折衷突变促进卵巢功能障碍和 头面部发育不良。与之形成鲜明对比的是，单个体细胞突变FOXL2C134W几乎 普遍存在于aGCT中，对400多名不同种族的患者进行了检查。我们证明了这一点 FOXL2基因是在颗粒细胞肿瘤中唯一发现的基因，是一种活性强的基因。然而，分子 FOXL2C134W致癌作用的基础尚不清楚，也不知道FOXL2C134W的作用 体内突变。绝经期或刚刚绝经后出现aGCT的患者，提示处于初始状态 这会促进肿瘤的发展。他们通常通过手术和相同的化疗进行治疗。 提供给其他无关类型的卵巢癌。出现晚期疾病或复发的患者， 做得不好。增加对aGCT的了解可能会为这些妇女的治疗提供见解。这 提案，由两位研究卵巢内分泌功能的专家合作的个人助理提交(岛崎) 和肿瘤形成和进展(Stupack)，由两个相辅相成的目的组成，旨在了解 FOXL2C134W与肿瘤发生目的1评价FOXL2C134W或FOXL2C130W原位表达的效果 (相当于小鼠)利用分离的小鼠卵泡在体外对完整和可接近的卵泡内GC功能的影响 器官培养。在目标2中，我们将直接测试FOXL2C134W表达对肿瘤形成的充分性，通过 在活体小鼠的成体阶段选择性地表达该基因。如果是这样的话，这将是第一款 直接证明这种突变的因果关系，并应为干预提供新的机会。