Adipokine Signaling as a Therapeutically Targetable Driver of Tumor Metabolism

项目概要： 肥胖和癌症之间的联系在流行病学上已经得到了很好的证实，但在临床上却知之甚少。 机械水平。透明细胞肾细胞癌（ccRCC）是肾癌的最常见形式，并且具有以下特征： 与代谢综合征有明显联系ccRCC同时表现出剧烈的代谢重新布线， 组织学和分子水平，最近已经发现是肿瘤发展所必需的。 然而，目前，ccRCC的护理标准是针对酪氨酸激酶的靶向治疗剂，包括 VEGF受体，在大多数情况下导致总体生存的适度改善。因此， 需要新的方法来治疗ccRCC，改变代谢可能提供临床有用的立足点。我们 研究了ccRCC的特征性脂质储存表型，并确定了一种分子机制， 部分原因是肥胖。本申请集中于由脂肪产生的可溶性脂肪因子， 抑制脂质代谢的肿瘤，并且是肿瘤生长所必需的。一个秘密组织的本质 因子导致诊断和治疗潜力，在这里，我们研究了抑制 脂肪因子，Chemerin，与多种方法，包括单克隆抗体在临床前动物模型， ccRCC和基因工程小鼠模型（GEMM）。我们还将剖析的行动机制， Chemerin在肿瘤和非肿瘤细胞上的表达，并检查Chemerin亚型在收集的肿瘤细胞中的意义。 临床标本总之，该提案的目的是验证ccRCC中的一个新目标， 与现有疗法相结合，以改善患者的治疗效果。

Project Summary: The link between obesity and cancer is well-established epidemiologically, but poorly understood at a mechanistic level. Clear cell renal cell carcinoma (ccRCC) is the most common form of renal cancer, and has clear ties with metabolic syndrome. ccRCC simultaneously demonstrates drastic metabolic rewiring at the histological and molecular levels that recently have been found to be essential for tumor development. Currently, however, the standard of care for ccRCC is targeted therapeutics against tyrosine kinases including the VEGF receptor, that in most cases lead to modest improvements in overall survival. Thus identification of new approaches to treat ccRCC is needed, and altered metabolism may offer a clinically useful foothold. We have investigated the characteristic lipid storage phenotype of ccRCC and identified a molecular mechanism that is driven in part by obesity. The present application focusses on a soluble adipokine produced by fat and tumors that suppresses lipid catabolism, and is essential for tumor growth. The very nature of a secreted factor leads to both diagnostic and therapeutic potential, and here we investigate the impact of inhibiting the adipokine, Chemerin, with multiple approaches including a monoclonal antibody in preclinical animal models of ccRCC, and a genetically engineered mouse model (GEMM). We will also dissect the mechanisms of action of Chemerin on tumor and non-tumor cells, and examine the significance of Chemerin isoforms in collected clinical specimens. Together, the aim of the proposal is to validate a novel target in ccRCC that could be combined with existing therapies to improve patient outcomes.