Metabolic Tumor Suppressors in Renal Cancer: Unprecedented Roles in Disease Progression

肾癌中的代谢肿瘤抑制剂：在疾病进展中发挥前所未有的作用

• 批准号: 9975793
• 负责人: M. CELESTE SIMON
• 金额: $ 95.99万
• 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: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975793
• 关键词: ARG2 gene; Ablation; Burkitt Lymphoma; Chemotherapy and/or radiation; Cholesterol Esters; Clear cell renal cell carcinoma; Copy Number Polymorphism; Data; Deposition; Diagnosis; Disease; Disease Progression; Enzymes; Excision; Exhibits; Fatty acid glycerol esters; Fructose-1,6-Bisphosphatase; Genetic; Genetic Transcription; Gluconeogenesis; Glycogen; Glycolysis; Homeostasis; Human; Hypoxia Inducible Factor; Incidence; KRAS2 gene; Kidney; Knowledge; Lipids; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolic Pathway; Molecular; Molecular Abnormality; Mus; Mutation; NADP; Neoplasm Metastasis; Nuclear; Nuclear Proteins; Oncogenic; Operative Surgical Procedures; Organelles; PTEN gene; Pathway interactions; Patients; Primary carcinoma of the liver cells; Production; Proto-Oncogene Proteins c-akt; Relapse; Renal Cell Carcinoma; Renal carcinoma; Research; Role; Secondary to; Soft tissue sarcoma; Structure; TP53 gene; Triglycerides; Tumor Suppressor Proteins; Tumor stage; United States; VHL mutation; Woman; argininosuccinate lyase; argininosuccinate synthase; cancer cell; cancer subtypes; exome sequencing; improved; men; metabolomics; novel; novel therapeutics; programs; radiation resistance; targeted treatment; therapeutic target; transcriptomics; tumor; tumor metabolism; tumorigenesis; urea cycle

Project Summary/Abstract Kidney cancer, or renal cell carcinoma (RCC), is among the ten most prevalent malignancies in the United States, and has exhibited an increasing incidence rate in both men and women since 2001. The most common subtype of RCC is “clear cell” RCC (ccRCC, 75% of all cases). ccRCC is characterized by chemotherapy and radiation resistance; while surgical resection of early stage disease can be curative, five year relapse rates approach 40%, with the majority of these cases developing metastases. Of note, ccRCCs lack common genetic abnormalities observed in many other human cancers, including mutations in the PTEN, AKT, TP53, and KRAS loci, hindering successful treatment of ccRCC by corresponding targeted therapies. In contrast, ccRCCs feature consistent metabolic abnormalities, such as highly elevated glycogen and fat deposition. These metabolic disorders are associated with normoxic stabilization of hypoxia-inducible factors (HIFs), secondary to von Hippel-Lindau (VHL mutations) that occur in > 90% of ccRCC tumors. Because Vhl ablation in mouse kidney fails to induce ccRCC formation, additional oncogenic changes may be required. By integrating exome sequencing, copy number variation, transcriptomic, and metabolomic data, we identified multiple metabolic enzymes as universally depleted in all ccRCC tumors (an otherwise genetically heterogeneous disease). The first pathway involves decreased gluconeogenesis and glycogen storage, as regulated by fructose-1,6-bisphosphatase (FBP1). FBP1 loss significantly correlates with advanced tumor stages and poor patient survival, consistent with its tumor suppressor functions in inhibiting glycolysis, NADPH production, and nuclear HIF activity. The second most down-regulated metabolic pathway in ccRCC is the urea cycle, including the argininosuccinate synthase 1 (ASS1), argininosuccinate lyase (ASL), and arginase 2 (ARG2) enzymes. Of note, FBP1, ASS1, and ASL have both catalytic activity-dependent and catalytic activity-indendent, or structural roles. For example, FBP1 exhibits both cytoplasmic metabolic activity and nuclear transcriptional effects on HIF and other nuclear proteins. We propose to investigate the unprecedented, non-catalytic roles of these enzymes in ccRCC and other cancers. ccRCC also exhibit unusually high numbers of lipid droplets, organelles which store triglycerides and cholesterol esters, whose overproduction is a hallmark of this disease. Delineating the molecular mechanisms by which changes in gluconeogenesis, the urea cycle, and lipid homeostasis alter ccRCC tumor metabolism will provide new therapeutic avenues to target a majority of patients diagnosed with this kidney cancer subtype. The results obtained from ccRCC will also be applied to other malignancies, including soft-tissue sarcoma, hepatocellular carcinoma, and Burkitt's lymphoma, which appear to engage in highly similar metabolic reprogramming.

项目摘要/摘要 肾癌或肾细胞癌（RCC）是曼联十大最普遍的恶性肿瘤之一 各州，自2001年以来，男性和女性的发病率均增加。最常见的 RCC的亚型是“透明细胞” RCC（CCRCC，占所有病例的75％）。 CCRC的特征是化学疗法和 辐射抗性；虽然早期疾病的手术切除可以治愈，但五年缓解率 接近40％，其中大多数发生转移。值得注意的是，CCRCS缺乏常见 在许多其他人类癌症中观察到的遗传异常，包括PTEN，AKT，TP53中的突变， 和Kras Loci，通过相应的靶向疗法阻碍了CCRCC的成功治疗。相比之下， CCRCC具有一致的代谢异常，例如高度升高的糖原和脂肪沉积。 这些代谢疾病与缺氧诱导因素（HIF）的正常稳定有关， 继发于von Hippel-Lindau（VHL突变），占CCRCC肿瘤的90％。因为VHL消融 在小鼠肾脏未能诱导CCRCC的形成中，可能需要额外的致癌变化。经过 整合外显子组测序，拷贝数变化，转录组和代谢组数据，我们确定了 在所有CCRCC肿瘤中普遍耗尽多种代谢酶（否则通常 异质疾病）。第一个途径涉及减少的糖化作用和糖原储存，如 由果糖1,6-二磷酸酶（FBP1）调节。 FBP1损失与晚期肿瘤显着相关 阶段和较差的患者生存期，与其肿瘤抑制剂在抑制糖酵解中的功能一致，NADPH 生产和核HIF活性。 CCRCC中第二个最下调的代谢途径是尿素 循环，包括精氨酸偶联合酶1（ASS1），精氨酸酶裂解酶（ASL）和精氨酸酶2 （arg2）酶。值得注意的是，FBP1，ASS1和ASL具有催化活性依赖性和催化性 活动引入或结构角色。例如，FBP1表现出细胞质代谢活性和 对HIF和其他核蛋白的核转录作用。我们建议调查 这些酶在CCRCC和其他癌症中的前所未有的非催化作用。 CCRC也展出 异常数量的脂质液滴，储存甘油三酸酯和胆固醇酯的细胞器，它们 生产过多是这种疾病的标志。描述分子机制的变化 糖异生，尿素周期和脂质稳态改变CCRCC肿瘤代谢将提供新的 针对大多数被诊断为肾癌亚型的患者的治疗途径。结果 从CCRCC获得的也将应用于其他恶性肿瘤，包括软组织肉瘤，肝细胞 癌和伯基特的淋巴瘤似乎进行了高度相似的代谢重编程。