Metabolic alterations in soft tissue sarcoma initiation and progression

项目摘要 软组织肉瘤(STSS)是一组高度多样化和研究不足的恶性肿瘤，其起源于 中胚层来源的组织，其来源尚不清楚，但可能包括间充质干细胞， 肌肉卫星细胞和成肌细胞。在美国，近2万人被诊断为性传播疾病， 约40%的患者因局部复发或远处转移而死亡。患有疾病的患者 未分化多形性肉瘤(UPS)是最具侵袭性的肉瘤亚型，其生存期为5年。 转移性疾病的发生率仅为24%。因此，对潜在的机制有更深的理解 UPS的启动和进展对于开发新的靶向肉瘤治疗以及改善 使用目前的治疗方法。 肉瘤与其他实体肿瘤非常相似，通常在低氧和/或营养不良的条件下生长旺盛， 为此，要实施适应机制，其中包括改变低氧诱导因子的表达 (HIF)在低氧下稳定下来，以促进在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 HIFs在改变STS新陈代谢方面的作用尚不完全清楚。《癌症》杂志的数据 基因组图谱显示肉瘤中涉及的蛋白的表达发生了显著的变化 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， 尤其是在维持全身葡萄糖动态平衡方面，强调葡萄糖-丙氨酸循环， 它的作用是将氨基和碳水化合物从肌肉输送到肝脏。此外，关键是 参与这一途径的转氨酶谷丙转氨酶(GPTs)在 相对于正常骨骼组织的STS(包括UPS)数量。 因此，我们对该提议的中心假设是，GPT S通过以下方式发挥肿瘤抑制作用 调节软组织肉瘤及邻近正常肌肉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：确定代谢变化 在肉瘤进展和转移中起重要作用。特定目标2：确定GPTs在调节肿瘤生长中的作用 STS.为了完成这些研究，我将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。这样做的总体目标是 该提案旨在加深我们对代谢改变如何促进肉瘤发生和发展的理解 进展，这将有助于确定治疗肉瘤患者的新治疗靶点。

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.