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

项目摘要/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，男女发病率均呈上升趋势。最常见的 肾细胞癌亚型为“透明细胞型”肾细胞癌(ccRCC，占全部病例的75%)。慢性肾细胞癌的特点是化疗和 抗辐射；虽然手术切除早期疾病是可以治愈的，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，中国农村信用社缺乏共同的 在许多其他人类癌症中观察到的遗传异常，包括PTEN，AKT，TP53， 和KRAS基因座，阻碍相应的靶向治疗成功。相比之下， CCRCC的特点是持续的代谢异常，如糖原高度升高和脂肪沉积。 这些代谢紊乱与常氧性低氧诱导因子(HIF)的稳定有关， 继发于von Hippel-Lindau(VHL突变)，它发生在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改变。通过 结合外显子组测序、拷贝数变异、转录和代谢组学数据，我们鉴定了 在所有ccRCC肿瘤中普遍耗尽的多种代谢酶(以其他方式遗传的 异质性疾病)。第一个途径涉及糖异生和糖原储存减少，如 受果糖-1，6-二磷酸酶(FBP1)调节。FBP1缺失与晚期肿瘤显著相关 分期和患者生存率差，与其抑制糖酵解、NADPH的肿瘤抑制功能一致 生产和核HIF活动。CcRCC中第二个最受下调的代谢途径是尿素。 周期，包括精氨酸琥珀酸合成酶1(ASS1)、精氨酸琥珀酸裂解酶(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和催化 活动-依存性或结构性角色。例如，FBP1既表现出细胞质代谢活性，又表现出 核转录对缺氧诱导因子和其他核蛋白的影响。我们建议调查 这些酶在肾细胞癌和其他癌症中发挥了前所未有的非催化作用。CcRCC还展出了 异常多的脂滴，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。描述了生物多样性变化的分子机制 糖异生、尿素循环和脂质平衡改变肾细胞癌的代谢将提供新的 针对大多数被诊断为这种肾癌亚型的患者的治疗途径。结果是 从ccrcc获得的信息也将应用于其他恶性肿瘤，包括软组织肉瘤、肝细胞癌 癌症和伯基特淋巴瘤，它们似乎进行了高度相似的代谢重新编程。

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.