Sirtuins and Cancer

项目摘要 结直肠癌（CRC）是美国癌症相关死亡的第二大原因， 存活率只有60%。与CRC相关的不良疾病结局强调了迫切需要 了解影响CRC发生和进展的细胞机制。的几 众所周知的CRC遗传驱动因子如KRas和PIK 3CA是代谢调节因子的主要调节因子， 在癌症发展过程中进行重编程。改变的肿瘤代谢促进了 分子对细胞生长，信号传导和存活很重要;然而，我们对细胞生长的精确知识， 在化疗耐药的CRC中调节代谢和存活的机制仍然不完整。 在协调新陈代谢与细胞存活和应激反应中起重要作用的一个蛋白质家族 是依赖NAD+的sirtuin超家族。我们的初步数据表明， 线粒体定位的sirtuin，SIRT 4，发生在CRC中，并导致核苷酸的重编程， 生物合成以使代谢物远离补救核苷酸代谢并从头上调 核苷酸生物合成我们假设这种代谢开关有助于增加CRC细胞 增殖和对化疗的抗性。我们的建议将在两个方面验证这一假设 互补，但独立的目标。首先，使用生物化学方法，目标1将检查 SIRT 4介导的代谢重编程增加细胞增殖的机制， 检查SIRT 4活性和底物。我们还将研究代谢副产物的作用 SIRT 4介导的活性的下游。接下来，目标2将测试临床相关的后果 使用类器官的CRC生理模型中的SIRT 4丢失，新型基因工程小鼠 模型和患者来源的异种移植物（PDX）模型。最后，我们将研究 SIRT 4在体内对CRC代谢和化疗抗性的损失。该项目将提供一个 在单细胞水平上绘制CRC中前所未有的代谢重编程图， 了解CRC代谢如何在化疗耐药性的背景下发生变化， 开发利用线粒体代谢来治疗疾病的新的治疗策略的大门 对化疗有抵抗力的癌症

Project Summary Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US, with a 5-year survival rate of only 60%. The poor disease outcome associated with CRC highlights an urgent need to understand the cellular mechanisms that influence initiation and progression of CRC. Several of the well-known genetic drivers of CRC such as KRas and PIK3CA are dominant regulators of metabolic reprogramming during cancer progression. Altered tumor metabolism facilitates generation of molecules important for cell growth, signaling, and survival; yet, our knowledge of the precise mechanisms that regulate metabolism and survival in chemotherapy resistant CRC remains incomplete. One family of proteins important in coordinating metabolism with cellular survival and stress responses is the NAD+-dependent sirtuin superfamily. Our preliminary data demonstrate that the loss of a mitochondrial localized sirtuin, SIRT4, occurs in CRC and results in the reprogramming of nucleotide biosynthesis to shift metabolites away from salvage nucleotide metabolism and upregulate de novo nucleotide biosynthesis. We hypothesize this metabolic switch contributes to increased CRC cell proliferation and resistance to chemotherapy. Our proposal will test this hypothesis in two complementary, but independent Aims. First, using a biochemical approach, Aim 1 will examine the mechanism by which SIRT4-mediated metabolic reprogramming increases cell proliferation by examining SIRT4 activity and substrates. We will also examine the role of the metabolic by-products downstream of SIRT4-mediated activity. Next, Aim 2 will test the consequence of clinically relevant SIRT4 loss in physiological models of CRC using organoids, novel genetically engineered mouse models, and patient derived xenograft (PDX) models. Finally, we will examine the consequences of SIRT4 loss on CRC metabolism and chemotherapy resistance in vivo. This project will provide an unprecedented map of metabolic reprogramming in CRC at a single cell level and improve understanding of how CRC metabolism changes in the context of chemotherapy resistance, opening the door for development of novel therapeutic strategies that leverage mitochondrial metabolism to treat chemotherapy resistant cancers.