Notch signaling in liposarcoma

脂肪肉瘤中的Notch信号传导

• 批准号: 9922668
• 负责人: Shihuan Kuang
• 金额: $ 35.46万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-13 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922668
• 关键词: Address; Adipocytes; Adipose tissue; Animal Model; Breast Osteosarcoma; Cell Communication; Cell Line; Cells; Data; Development; Drug Screening; Etiology; Exhibits; Foundations; Gene Expression; Genomics; Growth; Homeostasis; Human; Hyperglycemia; Insulin Resistance; Lead; Link; Lipodystrophy; Malignant - descriptor; Malignant Neoplasms; Metabolic; Metabolic dysfunction; Metabolism; Molecular; Mus; Oncogenic; Organ; PPAR gamma; Pathogenesis; Pathogenicity; Patients; Play; Process; Regulation; Reporting; Role; Seminal; Series; Signal Transduction; Soft Tissue Neoplasms; Therapeutic; Therapeutic Intervention; Time; Tissue Microarray; Transgenic Mice; Up-Regulation; Work; Xenograft procedure; adipocyte differentiation; adiponectin; base; cancer type; effective therapy; human migration; in vivo; inhibitor/antagonist; leukemia; lipid biosynthesis; liposarcoma; malignant breast neoplasm; mouse model; notch protein; novel; prevent; rosiglitazone; sarcoma; soft tissue; stem cell differentiation; tool; transcriptome sequencing; tumor; tumor xenograft; tumorigenesis; tumorigenic

Abstract Human liposarcoma (LPS) is a deadly and the most common soft tissue cancer whose cellular origin and molecular regulation are unclear. Using a novel transgenic mouse model, we made a seminal discovery in our unpublished preliminary results that aberrant activation Notch signaling in mature adipocytes drives their dedifferentiation and formation of LPS. Notch signaling is an evolutionarily conserved signal transduction cascade that plays an important role in development, cell-cell communication and stem cell differentiation. Aberrant Notch activity has been implicated in several types of cancers including leukemia, breast cancer and osteosarcoma but its role in LPS has not been reported. While our series of preliminary studies have established the adipocyte origin and pathogenic process of LPS in the mouse model, several imperative questions stood out to be addressed in the proposed work. First, we will distinguish the relative role of Notch activity and metabolic dysfunction – an accompanying feature of the LPS transgenic mouse model – in the development and pathogenesis of LPS. Second, we will investigate the role of Notch signaling in human liposarcomas. Third, we will dissect and molecular mechanisms underlying Notch-driven LPS based on our preliminary genomics and lipidomics results, and futher explore therapeutic interventions to treat the murine and human LPS in xenograft mouse models. Results from the proposed work will for the first time uncover the oncogenic function of Notch signaling in adipocytes and adipose tissue, one of the most important metabolic organs in the body. In addition, our transgenic mouse model will represent a unique tool to study the etiology, pathogenesis and treatment of human LPS.

摘要 人类脂肪肉瘤是一种致命的、最常见的软组织癌症，其细胞起源和 分子调控尚不清楚。使用一种新的转基因小鼠模型，我们在我们的 未发表的初步结果表明，成熟脂肪细胞中异常激活的Notch信号推动了他们的 内毒素的脱分化和形成。Notch信号是一种进化上保守的信号转导 在发育、细胞间通讯和干细胞分化中发挥重要作用的级联反应。 Notch活性异常与多种癌症有关，包括白血病、乳腺癌和 骨肉瘤，但其在脂多糖中的作用尚未见报道。虽然我们的一系列初步研究已经 建立小鼠脂肪细胞来源和内毒素致病过程的模型，几点势在必行 在拟议的工作中需要解决的问题很突出。首先，我们将区分Notch的相对角色 活动和代谢功能障碍-内毒素转基因小鼠模型的伴随特征-在 内毒素的发展和发病机制。第二，我们将研究Notch信号在人类中的作用 脂肪肉瘤。第三，我们将根据我们的研究结果，剖析Notch驱动的内毒素的分子机制 初步的基因组学和脂质组学结果，并进一步探索治疗小鼠的干预措施 人内毒素在异种移植小鼠模型中的表达。拟议工作的结果将首次揭示 Notch信号在脂肪细胞和脂肪组织中的致癌作用 身体里的器官。此外，我们的转基因小鼠模型将是研究病因学的独特工具， 人内毒素的发病机制及治疗。