Defining the role of menin in the Ewing sarcoma stress response

定义 menin 在尤文肉瘤应激反应中的作用

• 批准号: 10307995
• 负责人: Jennifer Andrea Jiménez
• 金额: $ 3.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307995
• 关键词: Amino Acids; Anabolism; Binding Proteins; Bioenergetics; Biological; Biology; Cancer Biology; Cell Proliferation; Cell Survival; Cells; Cellular Metabolic Process; Childhood; Chondrosarcoma; Complementary DNA; Connective and Soft Tissue Neoplasm; Data; Disease; Down-Regulation; EWS-FLI1 fusion protein; Epigenetic Process; Event; Ewings sarcoma; FRAP1 gene; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Hypoxia; In Vitro; Laboratories; Lead; Maintenance; Malignant Neoplasms; Mediating; Menin; Mesenchymal Cell Neoplasm; Mesenchymal Stem Cells; Messenger RNA; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Metastatic Ewing' s Sarcoma; Modeling; Modification; Molecular; Neoplasm Metastasis; Nutrient; Oncogene Activation; Oncogenes; Oncogenic; Oxidative Stress; Pathway interactions; Patients; Pharmacology; Proteins; Publishing; Regulation; Reporting; Role; Scaffolding Protein; Serine; Signal Transduction; Stimulus; Stress; Supporting Cell; Survival Rate; Testing; Translations; Tumor Suppressor Proteins; Tumorigenicity; Work; biological adaptation to stress; c-myc Genes; cancer cell; cell type; epigenetic regulation; experimental study; improved; in vitro Model; in vivo; innovation; insight; loss of function; mTOR Signaling Pathway; new therapeutic target; novel; novel therapeutics; nutrient deprivation; osteosarcoma; overexpression; programs; rapid growth; response; transcription factor; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY Cancer cells must respond to microenvironmental stress during tumor growth and metastasis in order maintain metabolic homeostasis and support cell survival. ATF4 is a stress-induced master transcription factor that is frequently upregulated in cancer. ATF4 activates gene expression programs that allow cells to respond to stresses, such as nutrient and amino acid limitation, hypoxia, and oxidative stress. Previously published work from the Lawlor lab revealed that the scaffolding protein menin promotes Ewing sarcoma tumorgenicity and identified metabolic and stress response pathways, including the serine biosynthesis pathway, as downstream targets of menin. Ewing sarcoma is a bone and soft tissue tumor that is most commonly driven by the EWS-FLI1 oncogene. Although survival rates for patients with localized tumors have improved, despite maximally intensive therapy, Ewing sarcoma remains lethal for a third of patients, and event free and overall survival rates for patients with metastatic disease are dismal. To this day, efforts to target the pathognomonic EWS-FLI1 fusion protein have been largely unsuccessful, requiring the identification novel therapeutic targets and strategies. The scaffolding protein menin can function as a tumor suppressor or as an oncogene in cancer. Menin can regulate gene expression in both epigenetic-dependent and -independent manners, depending on its interaction with several different protein-binding partners. Our preliminary data show that EWS-FLI1 contributes to regulation of menin and its control of cell metabolism. In particular, we have found that, in Ewing sarcoma, ATF4 is highly expressed and maintains Ewing sarcoma cell proliferation by regulating stress response pathways, including the serine synthesis pathway. In addition, our studies show that ATF4 expression is modulated by menin. This proposal will test the central hypothesis that a novel EWS-FLI1-menin-ATF4 axis functions in Ewing sarcoma to promote cellular adaptation to stress, and that this axis is required for maintenance of metabolic homeostasis and tumorgenicity. This hypothesis will be tested through two specific aims. Aim 1 will investigate the molecular mechanism(s) by which menin regulates ATF4 in Ewing sarcoma, and the biological significance of this axis in response to stress. Aim 2 will elucidate the contribution of the EWS-FLI1 oncogene to maintaining high-level menin expression as part of this stress-response axis. To accomplish these specific aims, menin, ATF4, and EWS-FLI1 gain and loss-of-function in vitro models; metabolic profiling; and in vivo metastasis models will be used to study the impact of EWS-FLI1 and/or menin modulation on ATF4-dependent Ewing sarcoma cell survival and response to stress. The results from these innovative studies will define cooperative mechanisms between EWS-FLI1 and menin in regulation of stress response pathways in Ewing sarcoma, with the overall goal of identifying new therapeutic opportunities. Elucidating the contribution of menin to cellular metabolic homeostasis will be of profound importance to cancer biology more broadly.

项目摘要 癌细胞必须在肿瘤生长和转移过程中对微环境应激做出反应，以维持其生长和转移。 代谢稳态和支持细胞存活。ATF 4是应激诱导的主转录因子， 在癌症中频繁上调。ATF 4激活基因表达程序，使细胞能够响应 应激，如营养和氨基酸限制、缺氧和氧化应激。以前发表的作品 来自Lawlor实验室的研究表明，支架蛋白menin促进尤文肉瘤的致瘤性， 确定了代谢和应激反应途径，包括丝氨酸生物合成途径，作为下游 的目标。尤文肉瘤是一种骨和软组织肿瘤，最常见的是由EWS-FLI 1 癌基因尽管局部肿瘤患者的生存率有所提高， 治疗，尤文肉瘤仍然有三分之一的患者是致命的，患者的无事件和总生存率 转移性疾病的患者情况很糟糕迄今为止，靶向特异性EWS-FLI 1融合蛋白的努力 在很大程度上是不成功的，需要确定新的治疗靶点和策略。的 支架蛋白menin可以在癌症中作为肿瘤抑制因子或致癌基因发挥作用。Menin可以调节 基因表达的表观遗传依赖和独立的方式，这取决于它的相互作用， 几种不同的蛋白质结合伴侣我们的初步数据表明，EWS-FLI 1有助于调节 menin及其对细胞代谢的控制。特别是，我们发现，在尤文肉瘤中，ATF 4高度表达。 表达和维持尤文肉瘤细胞增殖通过调节应激反应途径，包括 丝氨酸合成途径此外，我们的研究表明，ATF 4的表达是由menin调制。这 一项提案将检验一个新的EWS-FLI 1-menin-ATF 4轴在Ewing中起作用的中心假设 肉瘤，以促进细胞适应压力，这一轴是必要的维持 代谢稳态和致瘤性。这一假设将通过两个具体目标进行检验。要求1 将研究menin在尤文肉瘤中调节ATF 4的分子机制，以及其生物学特性。 这个轴的重要性，以应对压力。目的2将阐明EWS-FLI 1癌基因的作用 维持高水平的menin表达作为应激反应轴的一部分。为了实现这些具体的 目的，menin，ATF 4和EWS-FLI 1获得和功能丧失体外模型;代谢谱;和体内 转移模型将用于研究EWS-FLI 1和/或menin调节对ATF 4依赖性肿瘤的影响。 尤因肉瘤细胞存活与应激反应。这些创新研究的结果将定义 EWS-FLI 1与menin在尤因应激反应通路调控中的协同作用机制 肉瘤，总体目标是寻找新的治疗机会。阐明男性的贡献 对细胞代谢稳态的影响将对更广泛的癌症生物学具有深远的重要性。