Sirtuins and Cancer

项目摘要 在美国，结直肠癌(CRC)是癌症相关死亡的第二大原因， 存活率只有60%。与结直肠癌相关的不良疾病结局突出表明迫切需要 了解影响结直肠癌发生和发展的细胞机制。其中的几个 众所周知，KRAS和PIK3CA等结直肠癌的遗传驱动因素是代谢的主要调节因素 癌症进展过程中的重新编程。肿瘤新陈代谢改变促进了 对细胞生长、信号传递和生存很重要的分子；然而，我们对 对化疗耐药的结直肠癌的代谢和生存的调节机制仍不完整。 一个在协调新陈代谢、细胞生存和应激反应中起重要作用的蛋白质家族 是依赖NAD+的sirtuin超家族。我们的初步数据显示， 线粒体定位sirtuin，SIRT4，出现在结直肠癌中，并导致核苷酸的重新编程 生物合成使代谢物远离抢救核苷酸代谢并上调从头开始 核苷酸生物合成。我们假设这种代谢转换与结直肠癌细胞增多有关 增殖和对化疗的抗药性。我们的提案将分两个阶段检验这一假设 相辅相成，但目标独立。首先，使用生化方法，目标1将检查 SIRT4介导的代谢重编程促进细胞增殖的机制 检测SIRT4活性和底物。我们还将研究代谢副产物的作用。 SIRT4介导的活性下游。接下来，目标2将测试与临床相关的结果 利用有机化合物建立结直肠癌生理模型中SIRT4缺失的新基因工程小鼠 模型和患者来源的异种移植(PDX)模型。最后，我们将研究 SIRT4基因缺失对体内CRC代谢和化疗耐药的影响该项目将提供一个 在单细胞水平上史无前例的结直肠癌代谢重编程图谱和改善 了解化疗耐药背景下结直肠癌代谢的变化 开发利用线粒体新陈代谢治疗的新治疗策略的大门 化疗耐药癌症。

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.