Metabolic alterations in soft tissue sarcoma initiation and progression

软组织肉瘤发生和进展的代谢改变

• 批准号: 9329100
• 负责人: Pearl Lee
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329100
• 关键词: ARNT gene; Adult; Alanine; Amino Acids; Animal Model; Binding; Biological Assay; CRISPR/Cas technology; Cancer Cell Growth; Carbon; Catabolism; Cell Line; Cell Proliferation; Cells; Citric Acid Cycle; Contralateral; Data; Development; Diagnosis; Diet; Disease; Distant Metastasis; Environment; Enzymes; GPT gene; GPT2 gene; Gene Expression Profiling; Generations; Genes; Glucose; Glutamates; Glutamine; Growth; Human; Hypoxia; Hypoxia Inducible Factor; Immunohistochemistry; In Vitro; Individual; Injection of therapeutic agent; Liver; Malignant Neoplasms; Measures; Mediating; Mesenchymal Stem Cells; Mesoderm; Metabolic; Metabolic stress; Metabolism; Metastatic Neoplasm to the Lung; Methods; Modeling; Molecular Biology; Monitor; Mus; Muscle; Muscle Cells; Muscle satellite cell; Myoblasts; Neoplasm Metastasis; Nutrient; Oxidative Phosphorylation; Oxygen; Pathway interactions; Patients; Play; Primary Neoplasm; Process; Pyruvate; Recurrence; Role; Sampling; Skeletal Muscle; Soft tissue sarcoma; Solid Neoplasm; Stable Isotope Labeling; Survival Rate; System; Tail; The Cancer Genome Atlas; Tissues; Transaminases; Tumor Suppressor Proteins; Tumor-Derived; Undifferentiated; United States; Veins; aerobic glycolysis; amino acid metabolism; amino group; base; biobank; blood glucose regulation; improved; in vivo; in vivo Model; liver metabolism; macromolecule; metabolomics; mouse model; new therapeutic target; novel; protein expression; sarcoma; skeletal tissue; transamination; tumor; tumor growth; tumor xenograft; tumorigenesis

Project Summary Soft tissue sarcomas (STSs) are a highly diverse and understudied group of malignancies arising from mesoderm-derived tissues, where the cell of origin is unclear, but likely includes mesenchymal stem cells, muscle satellite cells and myoblasts. In the United States, nearly 20,000 individuals are diagnosed with STS, which is fatal for ~40% of patients due to either loco-regional recurrence or distant metastasis. Patients with undifferentiated pleomorphic sarcoma (UPS), the most aggressive sarcoma subtype, have a 5-year survival rate of only 24% with metastatic disease. Therefore, a deeper understanding of the mechanisms underlying UPS initiation and progression is critical to develop novel targeted sarcoma treatments, as well as improve the use of current therapies. Sarcomas, much like other solid tumors, typically thrive in hypoxic and/or nutrient poor conditions and to do so, implement adaptive mechanisms, which include the altered expression of hypoxia inducible factors (HIFs) that are stabilized under low O2 to promote survival in oxygen and nutrient limiting cellular environments. Notably, metabolic differences between normal muscle tissue and soft tissue sarcomas have been incompletely characterized, as well as the role of HIFs to alter STS metabolism. Data from The Cancer Genome Atlas demonstrate that sarcomas show significant changes in the expression of proteins involved in amino acid breakdown compared to normal skeletal tissue. The importance of muscle amino acid metabolism, particularly in maintaining whole body glucose homeostasis, is emphasized by the glucose-alanine cycle, which acts to transport amino groups and carbons from the muscle to the liver. Furthermore, the key transaminases involved in this pathway, glutamate-pyruvate transaminases (GPTs), are underexpressed in a number of STSs (including UPS) relative to normal skeletal tissue. Therefore, our central hypothesis of this proposal is that GPT s act as tumor suppressors by modulating amino acid and glycolytic metabolism in soft tissue sarcomas and adjacent normal muscle. Based on these hypotheses, I will pursue two specific aims. Specific Aim 1: determine the metabolic alterations in sarcoma progression and metastasis. Specific Aim 2: define the role of GPTs in mediating tumor growth in STS. To complete these studies, I will combine in vitro and in vivo methods of molecular biology, metabolomics, immunohistochemistry, animal modelling, and patient material. The overall objective of this proposal is to further our understanding of how metabolic alterations can promote sarcoma initiation and progression, which will help identify novel therapeutics targets to treat sarcoma patients.

项目摘要 软组织肉瘤（STS）是一组高度多样化和研究不足的恶性肿瘤， 中胚层来源的组织，其中细胞来源不清楚，但可能包括间充质干细胞， 肌卫星细胞和成肌细胞。在美国，近20，000人被诊断患有STS， 由于局部区域复发或远处转移，约40%的患者是致命的。患者 未分化多形性肉瘤（UPS）是最具侵袭性的肉瘤亚型， 只有24%的转移性疾病。因此，更深入地了解其背后的机制 UPS的启动和进展对于开发新的靶向肉瘤治疗以及改善肿瘤的生物学特性至关重要。 目前的治疗方法。 肉瘤，很像其他实体瘤，通常在缺氧和/或营养不良的条件下生长， 为此，实施适应性机制，包括改变缺氧诱导因子的表达 （HIF）在低氧下稳定，以促进氧气和营养限制细胞中的存活 环境.值得注意的是，正常肌肉组织和软组织肉瘤之间的代谢差异， 尚未完全表征，以及HIF改变STS代谢的作用。癌症数据 基因组图谱表明，肉瘤显示出与肿瘤相关的蛋白质表达的显著变化， 与正常骨骼组织相比，氨基酸分解。肌肉氨基酸代谢的重要性， 特别是在维持全身葡萄糖稳态方面，通过葡萄糖-丙氨酸循环来强调， 其作用是将氨基和碳从肌肉运输到肝脏。此外，钥匙 参与这一途径的转氨酶，谷氨酸-丙酮酸转氨酶（GPT），在细胞中表达不足。 相对于正常骨骼组织的STS（包括UPS）数量。 因此，我们的中心假设是，谷丙转氨酶作为肿瘤抑制剂， 调节软组织肉瘤和邻近正常肌肉中的氨基酸和糖酵解代谢。 基于这些假设，我将追求两个具体目标。具体目标1：确定代谢改变 肉瘤进展和转移。具体目标2：确定GPT在介导肿瘤生长中的作用， STS.为了完成这些研究，我将联合收割机结合体外和体内的分子生物学方法， 代谢组学、免疫组织化学、动物模型和患者材料。本报告的总体目标 我们的建议是进一步了解代谢改变如何促进肉瘤的发生， 进展，这将有助于确定新的治疗靶点来治疗肉瘤患者。