Double Duty: Elucidating the Effects of Estrogen on Tumor Cells and their Microenvironment in Lymphangioleiomyomatosis

项目摘要 淋巴管肌瘤病(LAM)是一种罕见的肺部疾病，其特征是 对雌激素敏感的转移性平滑肌细胞样腺瘤生长缓慢，导致囊性肺变 和肺功能的丧失。而由于TSC1或TSC2的缺失而导致的mTORC1去抑制介导了 在这种恶性发展过程中，雌激素在促进LAM肿瘤生长中起着关键作用。《哈姆斯》 实验室为LAM建立了一个小鼠模型，TSC2在雌性动物的子宫中被特异性地敲除 老鼠。这些动物发生了雌激素敏感的子宫肌层肿瘤，这些肿瘤具有LAM的大部分特征 肿瘤细胞。有趣的是，50%的动物发生了肺转移，这表明LAM细胞可能来自 子宫肌层，从而解释了LAM的性别二型性和雌激素敏感性。重要的是，虽然 TSC2缺失的体内肿瘤对雌二醇非常敏感，TSC2缺失的细胞系只有轻微的雌激素- 敏感，这表明雌激素可能在促进肿瘤生长的TSC2缺失细胞之外发挥作用。 本研究建议重点探讨雌二醇在促进LAM进展中潜在的双重效应作用。 该研究策略旨在检查LAM细胞的雌激素调节以及它们的 微环境。该提案特别集中在粒细胞髓系来源的雌激素作用上。 抑制细胞，在子宫特异性TSC2基因缺失小鼠的血液和子宫中显著升高，并发挥作用 在促进肿瘤进展方面发挥重要作用，可能是以雌激素依赖的方式。这些研究将 利用新的小鼠模型、TSC2基因缺失的异种移植、体外骨髓刺激试验等 确定雌激素直接和间接促进TSC2缺失细胞生长的机制 促进髓系来源的抑制细胞的产生和作用。这一奖学金将为一名 合格的候选人进入内科科学家的职业生涯。哈姆斯实验室有广泛的背景 癌症研究、小鼠遗传学和类固醇信号。实验室的范围随着它的发展不断扩大 探索先天免疫在癌症模型中的作用。此外，申请人还收集了一份咨询意见 由激素信号、炎症和肿瘤免疫学专家组成的委员会。她的训练计划 包括道德、领导力和专业发展方面的课程，以及研究研讨会、国家 会议和一对一指导。她已经为实现这些目标做了最优的定位， 哈姆斯博士的指导，他是一位模范内科科学家，有成功培训的长期记录 基础研究和翻译研究中的研究人员。罗切斯特的制度环境强调和 支持合作研究，并投资于培训未来的医生和科学家。《知识》 从这项研究中获得的成果将推进LAM研究领域，提出以雌激素为中心的战略 治疗，并加强致力于成为内科科学家的年轻实习生的职业发展。

Project Summary Affecting almost exclusively women, lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by estrogen-sensitive metastatic smooth muscle cell-like adenomas that grow slowly, resulting in cystic lung change and loss of pulmonary function. While mTORC1 disinhibition due to loss of TSC1 or TSC2 mediates the development of this malignancy, estrogen play a key role in promoting LAM tumor growth. The Hammes laboratory created a mouse model for LAM whereby TSC2 was specifically knocked out in the uterus of female mice. These animals developed estrogen-sensitive myometrial tumors that shared most characteristics of LAM tumor cells. Interesting, 50% of animals developed lung metastasis, suggesting that LAM cells may come from the myometrium, thus explaining the sexual dimorphism and estrogen sensitivity of LAM. Importantly, while TSC2-null in-vivo tumors were markedly sensitive to estradiol, TSC2-null cell lines are only mildly estrogen- sensitive, suggesting that estrogen may have actions outside of the TSC2-null cells that promote tumor growth. This research proposal focuses on the potential dual effector function of estradiol in promoting LAM progression. The research strategy is designed to examine estrogen modulation of LAM cells as well as their microenvironment. The proposal concentrates specifically on estrogen actions in granulocytic myeloid-derived suppressor cells, which are markedly elevated in the blood and uteri of uterine-specific TSC2-null mice and play a significant role in promoting tumor progression, likely in an estrogen-dependent fashion. These studies will utilize the novel mouse model, TSC2-null xenografts, in-vitro bone marrow stimulation assays, and other methods to determine mechanisms by which estrogen directly promotes TSC2-null cell growth and indirectly promotes myeloid derived suppressor cell production and actions. This fellowship will provide a path for a highly qualified candidate into a career as a physician scientist. The Hammes laboratory has an extensive background in cancer research, mouse genetics, and steroid signaling. The scope of the lab is continuously expanding as it explores the role of innate immunity in cancer models. In addition, the applicant has assembled an advisory committee comprised of experts in hormone signaling, inflammation, and tumor immunology. Her training plan includes courses in ethics, leadership and professional development, as well as research seminars, national meetings and one-on-one instruction. She has positioned herself optimally to achieve these goals under the mentorship of Dr. Hammes, a role model physician scientist with a long track record of training successful investigators in basic and translational research. The institutional environment at Rochester emphasizes and supports collaborative research and is invested in training future physicians and scientists. The knowledge gained from this fellowship will advance the field of LAM research, propose an estrogen-centered strategy for treatment, and fortify the career development of a young trainee devoted to being a physician scientist.