Notch signaling in liposarcoma

脂肪肉瘤中的Notch信号传导

• 批准号: 10158456
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158456
• 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; 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; lipidomics; liposarcoma; malignant breast neoplasm; mouse model; notch protein; novel; patient derived xenograft model; 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 Using a novel transgenic mouse model, we made a seminal discovery in our unpublished preliminary results that aberrant activation Notch signaling in mature adipocytes drives their dedifferentiation and formation of LPS.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.

抽象的 人脂肪肉瘤（LPS）是一种致命，最常见的软组织癌，其细胞起源和 分子调节尚不清楚。使用新型的转基因鼠标模型，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置口信号传导驱动其 LPS的去分化和形成。 Notch信号传导是一种进化配置的信号转导 级联在发育，细胞通信和干细胞分化中起重要作用。 异常缺口活动已在多种类型的癌症中实施，包括白血病，乳腺癌和 骨肉瘤，但尚未报道其在LPS中的作用。而我们的一系列初步研究已经 在小鼠模型中建立了LPS的脂肪细胞起源和致病过程，有几个势在必行 拟议工作中要解决的问题要停止。首先，我们将区分Notch的相对作用 活动和代谢功能障碍 - LPS转基因小鼠模型的参与特征 - LPS的发展和发病机理。其次，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 初步基因组学和脂质组学结果，并探索热干预措施以治疗鼠 和人体LPS中的鼠标模型。拟议工作的结果将首次发现 Notch信号传导在脂肪细胞和脂肪组织中的致癌功能，这是最重要的代谢之一 体内器官。此外，我们的转基因小鼠模型将代表研究病因的独特工具， 人LP的发病机理和治疗。

项目成果

Adipocyte dedifferentiation in health and diseases.

• DOI: 10.1042/cs20190128
• 发表时间: 2019-10
• 期刊: Clinical science
• 影响因子: 6
• 作者: Tongxing Song;S. Kuang

FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.

• DOI: 10.1038/s41467-023-41988-y
• 发表时间: 2023-10-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Qiu, Jiamin;Yue, Feng;Zhu, Peipei;Chen, Jingjuan;Xu, Fan;Zhang, Lijia;Kim, Kun Ho;Snyder, Madigan M.;Luo, Nanjian;Xu, Hao-wei;Huang, Fang;Tao, W. Andy;Kuang, Shihuan
• 通讯作者: Kuang, Shihuan

In Vitro Evaluation of Clinical Candidates of γ-Secretase Inhibitors: Effects on Notch Inhibition and Promoting Beige Adipogenesis and Mitochondrial Biogenesis.

• DOI: 10.1007/s11095-020-02916-7
• 发表时间: 2020-09-04
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Huang D;Qiu J;Kuang S;Deng M
• 通讯作者: Deng M

Transcriptome and Mass-Spectrometry-Based Lipidome Reveal a Role of PRMT5 in Membrane Transport and Cholesterol Synthesis in White Adipocytes.

基于转录组和质谱的脂质组揭示了 PRMT5 在白色脂肪细胞膜运输和胆固醇合成中的作用。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Chen,Xiyue;Jia,Zhihao;Fang,Shuyi;Yue,Feng;Ferreria,ChristinaR;Wan,Jun;Kuang,Shihuan
• 通讯作者: Kuang,Shihuan