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

项目总结/摘要 肾癌或肾细胞癌（RCC）是美国十大最常见的恶性肿瘤之一。 自2001年以来，男性和女性的发病率都在上升。最常见的 RCC的亚型是“透明细胞”RCC（ccRCC，所有病例的75%）。ccRCC的特征在于化疗， 放射抗性;虽然手术切除早期疾病可以治愈，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缺乏共同的 在许多其他人类癌症中观察到的遗传异常，包括PTEN，AKT，TP 53， 和KRAS基因座，阻碍通过相应的靶向疗法成功治疗ccRCC。与此相反的是， ccRCC具有一致的代谢异常，例如高度升高的糖原和脂肪沉积。 这些代谢紊乱与低氧诱导因子（HIF）的常氧稳定相关， 继发于von Hippel-Lindau（VHL突变），发生在> 90%的ccRCC肿瘤中。因为Vhl消融 在小鼠肾脏未能诱导ccRCC形成的情况下，可能需要额外的致癌变化。通过 整合外显子组测序、拷贝数变异、转录组学和代谢组学数据，我们确定了 多种代谢酶在所有ccRCC肿瘤中普遍耗尽（否则遗传学上是一种代谢酶）。 异质性疾病）。第一种途径涉及减少糖原合成和糖原储存， 由果糖-1，6-二磷酸酶（FBP 1）调节。FBP 1缺失与晚期肿瘤显著相关 阶段和患者生存率差，与其抑制糖酵解、NADPH 生产和核HIF活性。ccRCC中第二个下调最多的代谢途径是尿素 环，包括氨基琥珀酸合成酶1（ASS 1）、氨基琥珀酸裂解酶（ASL）和氨基琥珀酸裂解酶2 （ARG 2）酶。值得注意的是，FBP 1、ASS 1和ASL具有催化活性依赖性和催化活性依赖性。 独立于活动或结构的角色。例如，FBP 1表现出细胞质代谢活性和 核转录对HIF和其他核蛋白的影响。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。ccRCC还展示了 异常高数量的脂滴，储存甘油三酯和胆固醇酯的细胞器， 生产过剩是这种疾病的标志。描述了细胞内蛋白质的变化 肿瘤发生、尿素循环和脂质稳态改变ccRCC肿瘤代谢将提供新的 治疗途径，以针对大多数被诊断患有这种肾癌亚型的患者。结果 从ccRCC获得的新的抗肿瘤药物也将应用于其他恶性肿瘤，包括软组织肉瘤、肝细胞癌、 癌和伯基特淋巴瘤，它们似乎参与高度相似的代谢重编程。

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.