FOXL2 in Adult Granulosa Cell Tumorigenesis

FOXL2 在成人颗粒细胞肿瘤发生中的作用

基本信息

批准号：
10401465
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
项目类别：
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/10401465
关键词：
3-Dimensional Activins Adult Aging Agonist Aromatase Aromatase Inhibitors Bioinformatics Biology Cell Culture Techniques Cell physiology Cells Cellular biology Craniofacial Abnormalities Dependence Detection Development Diagnosis Disease Doxycycline Endocrine Endometrial Environment Enzymes Estrogen Receptor beta 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 Menopause 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 Pharmacology Physiological Postmenopause Radiation 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 preclinical development prevent prognostic reproductive tract selective expression sex standard of care theca cell transcription factor transcriptome tumor tumorigenesis

项目摘要

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.

项目摘要成年颗粒细胞肿瘤（AGCTS）占20个卵巢癌中的大约1个，由荷尔蒙形成活性卵泡驻留的细胞负责排卵。 AGCT通过伪造手术治疗骨盆辐射的可能性。没有标准的全身化疗。复发经常出现诊断后的十年，剩下的治疗是由就读肿瘤学家酌情决定的。 Foxl2是一个叉状转录因子家族的进化保守成员，对于性腺至关重要发展。 FOXL2基因中有100多个折衷突变促进卵巢功能障碍和颅面误导。与之形成鲜明对比的是，一个躯体突变，FoxL2C134W几乎发生在400多名各种种族的患者中，经过普遍的AGCT。我们证明了这一点在颗粒细胞肿瘤中独特发现的FOXL2基因是活跃而有效的。但是，分子 FOXL2C134W的致癌作用的基础尚不清楚，并且对该作用一无所知体内突变。患者出现在更年期时或过去的AGCT，这表明有启动情况这促进了肿瘤的发展。它们通常接受手术和相同的化学疗法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。对AGCT的越来越多的了解可以为治疗这些妇女提供见解。这提案，由两个合作的PIS提交，他们是研究卵巢内分泌功能（Shimasaki）的专家以及肿瘤的形成和进展（Stupack），包括两个补充旨在了解的作用肿瘤发生中的FOXL2C134W。 AIM 1将评估FOXL2C134W或FOXL2C130W的原位表达的影响（鼠标等效）在完整且可访问的卵泡中使用孤立的鼠标卵泡的GC功能器官培养。在AIM 2中，我们将直接测试FOXL2C134W表达的充分性，以通过该基因在活小鼠的成年阶段选择性地表达GC。如果是这样，这将是第一个模型直接证明了这种突变的因果关系，应该为干预提供新的机会。