The Origin and Cellular Heterogeneity of Uterine Leiomyomas

子宫平滑肌瘤的药物治疗受到我们对子宫平滑肌瘤的认识的限制， 这些肿瘤的起源和演变，以及分子异质性的程度。平滑肌瘤，也 子宫肌瘤是子宫平滑肌细胞最常见的良性肿瘤， 美国妇女发病的原因。以前的研究表明，肌瘤是 单克隆起源。然而，平滑肌瘤的组织学和细胞分选分析显示， 在平滑肌瘤肿瘤中，除了平滑肌细胞外，还存在成纤维细胞。 我们小组和其他人的全外显子组方法已经确定了介导复合物中的突变 亚基12（MED 12）在大约70%的LM患者中表达，表明MED 12突变细胞可能产生 上升为平滑肌瘤。我们建立了一个小鼠模型，显示子宫平滑肌瘤肿瘤形成， 表达Med 12突变。我们将利用我们的小鼠模型开始平滑肌瘤早期起源的研究 并与P50应用的其他项目相互作用，以确定平滑肌瘤的分子异质性 以及它们与肿瘤基因型的关系。我们的研究将集中在：1）了解发病和 Med 12突变阳性平滑肌瘤的进展，2）子宫内膜癌基因组不稳定性的演变 了解平滑肌瘤基因型与分子水平的关系 可能影响平滑肌瘤复发率和对治疗无反应性的异质性。我们 小鼠模型和初步研究结果将补充其他研究人员在这一P50 应用程序.我们将向布伦博士的项目1提供我们的小鼠模型和体内初步数据， Med 12与孕酮通路相互作用，并补充了他对不同人类的研究。 平滑肌瘤细胞类型与我们自己的研究在小鼠和人类。查克拉瓦蒂博士的三号计划 从我们对MED 12阳性、HMGA 2阳性和MED 12/HMGA 2阴性的单细胞测序中， 并将补充他对HMGA 2阳性平滑肌瘤的表观遗传学研究。统称 我们和我们的合作者提出的研究将为我们提供对疾病病理生理学的深刻见解。 子宫LM我们的研究将确定Med 12阳性平滑肌瘤的起源，确定基因型是否驱动 分子表型和细胞异质性，目的是推动平滑肌瘤的靶向治疗。

Pharmacologic therapies for uterine leiomyomas are hampered by our limited knowledge regarding the origin and evolution of these tumors, as well as the degree of molecular heterogeneity. Leiomyomas, also known as fibroids, are the most common benign tumors of uterine smooth muscle cells and are a major cause of morbidity among American women. Previous studies have suggested that fibroids are monoclonal in origin. However, histological and cell sorting analyses of leiomyomas have shown cellular heterogeneity, with presence of fibroblasts in addition to the smooth muscle cells in leiomyoma tumours. Whole exome approaches from our group and others have identified mutations in the mediator complex subunit 12 (MED12) in approximately 70% of LM patients, indicating that MED12 mutant cells might give rise to leiomyomas. We generated a mouse model that showed leiomyoma tumor formation in uteri that express Med12 mutation. We will utilize our mouse models to begin the study of leiomyoma early origins and interact with other Projects of this P50 application, to define molecular heterogeneity of leiomyomas and their relation to the tumor genotype. Our studies will focus to: 1) understand the onset and progression of Med12 mutation positive leiomyomas, 2) the evolution of genomic instability in uterine leiomyomas, and 3) understand the relationship between leiomyoma genotype and molecular heterogeneity that may impact leiomyoma recurrence rates and non-responsiveness to therapy. Our mouse model and preliminary findings will complement studies of other investigators in this P50 application. We will provide Dr. Bulun's Project 1 with our mouse model and in vivo preliminary data that Med12 interacts with the progesterone pathway, as well as complement his studies on different human leiomyoma cell types with our own studies in mice and humans. Dr. Chakravarti's Project 3 will benefit from our single cell sequencing on MED12 positive, HMGA2 positive, and MED12/HMGA2 negative leiomyomas and will complement his epigenetic studies on HMGA2 positive leiomyomas. Together, the studies proposed by us and our collaborators will provide great insights into the pathophysiology of uterine LM. Our studies will identify origin of Med12 positive leiomyomas, determine if genotype drives molecular phenotype and cellular heterogeneity, with a goal of driving targeted therapy for leiomyomas.