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

基本信息

批准号：
10456722
负责人：
M. CELESTE SIMON
金额：
$ 94.07万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456722
关键词：
ARG2 gene Ablation Burkitt Lymphoma Chemoresistance 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 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

项目摘要

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.

项目概要/摘要肾癌或肾细胞癌 (RCC) 是美国十种最常见的恶性肿瘤之一自 2001 年以来，男性和女性的发病率均呈上升趋势。最常见 RCC 亚型是“透明细胞”RCC（ccRCC，占所有病例的 75%）。抗辐射；虽然早期疾病的手术切除可以治愈，但五年复发率接近 40%，其中大多数病例发生转移。值得注意的是，ccRCC 缺乏共同点。在许多其他人类癌症中观察到的遗传异常，包括 PTEN、AKT、TP53、和 KRAS 基因座，阻碍了相应的靶向治疗成功治疗 ccRCC。 ccRCC 具有一致的代谢异常特征，例如糖原高度升高和脂肪沉积。这些代谢紊乱与缺氧诱导因子 (HIF) 的正常含氧量稳定有关，继发于 von Hippel-Lindau（VHL 突变），发生于 > 90% 的 ccRCC 肿瘤中，因为 Vhl 消融。小鼠肾脏中的 ccRCC 不能诱导 ccRCC 形成，可能需要额外的致癌变化。整合外显子组测序、拷贝数变异、转录组学和代谢组学数据，我们确定多种代谢酶在所有 ccRCC 肿瘤中普遍耗尽（否则遗传上第一个途径涉及糖异生和糖原储存的减少，如受果糖-1,6-二磷酸酶 (FBP1) 调节，FBP1 缺失与晚期肿瘤显着相关。分期和患者生存率低，与其抑制糖酵解、NADPH 的肿瘤抑制功能一致 ccRCC 中第二大下调的代谢途径是尿素。循环，包括精氨基琥珀酸合酶 1 (ASS1)、精氨基琥珀酸裂解酶 (ASL) 和精氨酸酶 2 (ARG2) 酶值得注意的是，FBP1、ASS1 和 ASL 都具有催化活性依赖性和催化性。例如，FBP1 表现出细胞质代谢活性和结构作用。我们建议研究 HIF 和其他核蛋白的核转录效应。这些酶在 ccRCC 和其他癌症中也表现出前所未有的非催化作用。异常大量的脂滴、储存甘油三酯和胆固醇酯的细胞器，其生产过剩是这种疾病的一个标志，描述了变化的分子机制。糖异生、尿素循环和脂质稳态改变 ccRCC 肿瘤代谢将提供新的针对大多数被诊断患有这种肾癌亚型的患者的治疗途径。从 ccRCC 获得的技术也将应用于其他恶性肿瘤，包括软组织肉瘤、肝细胞瘤癌和伯基特淋巴瘤，它们似乎参与高度相似的代谢重编程。