THE EVOLUTION OF PGD ADDICTION IN HUMAN PANCREATIC CANCER

人类胰腺癌 PGD 成瘾的演变

• 批准号: 10543775
• 负责人: Oliver Gene McDonald
• 金额: $ 35.46万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543775
• 关键词: 3-Dimensional; Acceleration; Acetyl Coenzyme A; Back; Bypass; Cancer Etiology; Catalysis; Cell physiology; Cells; Cessation of life; Chemicals; Chromatin; Circulation; Consumption; Conversion disorder; Coupled; DNA Sequence; Data; Dependence; Diagnosis; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant Metastasis; Enzymes; Epigenetic Process; Evolution; FASN gene; Fatty Acids; G6PD gene; Gene Expression; Genes; Genetic Transcription; Glucose; Growth; Human; Hypoglycemia; Knowledge; Learning; Left; Link; Liver; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Metabolic Pathway; Metabolism; Modification; Mutate; NADP; Names; Natural Selections; Neoplasm Metastasis; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pentosephosphate Pathway; Phosphogluconate Dehydrogenase; Preclinical Testing; Primary Neoplasm; Production; Reaction; Recurrence; Recycling; Repression; Research Design; Research Methodology; Resistance; Route; Series; Specificity; TXNIP gene; Testing; Tissues; Tumor Promotion; Western World; Work; addiction; cancer cell; cofactor; design; effective therapy; epigenome; epigenomics; experimental study; fatty acid biosynthesis; fatty acid metabolism; fitness; genetic selection; histone acetyltransferase; individual patient; insight; manufacture; non-genetic; overexpression; pancreatic cancer cells; pancreatic neoplasm; programs; small molecule inhibitor; sugar; therapeutic target; therapy resistant; transcriptome; treatment strategy; tumor growth; tumorigenesis

PROJECT SUMMARY (ABSTRACT) Distant metastasis is the cause of most cancer deaths. This is particularly true for pancreatic cancer. These patients develop hundreds to thousands of metastases that appear suddenly and progress rapidly to fill the liver and lungs. This stage of the disease is rapidly lethal, poorly understood, and grossly understudied. Long-term Objectives: Characterize what drives and/or accelerates the metastatic stage of pancreatic cancer in patients, and use this knowledge to design new and effective treatment strategies. Research Design: This proposal is designed to deeply characterize how a metabolic enzyme named PGD drives pancreatic cancer metastasis. We recently discovered that sugar (glucose) activates PGD, and once PGD is activated it strongly stimulates metastatic tumor growth. Understanding how cancer cells use glucose to activate PGD and how PGD then promotes tumor growth is important: it could lead to the first effective treatment strategies against the most common and most lethal stage of disease progression. Research Methods: Experiments will use a powerful set of metastatic pancreatic cancer cells and tissues that were collected from individual patients who died of the disease. Unique three-dimensional experimental platforms will allow us to investigate how these cancers learned to form metastatic tumors in the patients. Experiments will specifically focus on how the metastatic cells process glucose into metabolites that activate the PGD enzyme, and how the activated PGD enzyme is then able to enhance metastatic tumor growth. Aim 1: Determine how glucose fuels high PGD catalytic activity in distant metastases. Aim 1 will investigate how an unusual series of metabolic reactions convert glucose into metabolites that activate PGD. Our recent work was the first to detect these reactions in humans. That is because they are only operational in the metastatic cancer cells. Their function is to support PGD-driven metastasis. Aim 2: Define the mechanism whereby PGD is constitutively activated in distant metastases. Aim 2 will investigate how activated PGD is able to accelerate the rates of both glucose consumption and fatty acid biosynthesis in the metastatic cancer cells. This not only strongly promotes metastatic tumor growth, but also maintains PGD in a perpetually activated state that cannot be switched off in the presence of glucose. Aim 3: Investigate how PGD reprograms the epigenome to activate the metastatic transcriptome. Aim 3 will investigate how PGD is able to control the “epigenome”, which refers to small chemical modifications within chromatin that regulate expression of the genes encoded in the DNA sequence (the “transcriptome”). PGD reprograms the pancreatic cancer epigenome by accelerating glucose consumption. The metastatic cells break the extra glucose down into the smaller epigenetic chemicals. The chemicals are then used to increase expression of numerous genes that enhance metastatic tumor growth and bestow treatment resistance.

项目概要（摘要） 远处转移是大多数癌症死亡的原因。这对于胰腺癌来说尤其如此。这些 患者发生数百至数千个转移，这些转移突然出现并迅速进展，以填充肿瘤。 肝脏和肺这个阶段的疾病是迅速致命的，了解甚少，研究严重不足。 长期目标：描述驱动和/或加速胰腺癌转移阶段的因素 并利用这些知识来设计新的有效的治疗策略。 研究设计：该提案旨在深入表征一种名为PGD的代谢酶 导致胰腺癌转移我们最近发现，糖（葡萄糖）激活PGD，一旦 PGD被激活，它强烈刺激转移性肿瘤生长。了解癌细胞如何利用葡萄糖 激活PGD以及PGD如何促进肿瘤生长是重要的：它可能导致第一个有效的 针对疾病进展的最常见和最致命阶段的治疗策略。 研究方法：实验将使用一组强大的转移性胰腺癌细胞和组织， 是从死于这种疾病的病人身上收集的。独特的三维实验 这些平台将使我们能够研究这些癌症是如何在患者体内形成转移性肿瘤的。 实验将特别关注转移细胞如何将葡萄糖加工成代谢物， PGD酶，以及活化的PGD酶如何能够增强转移性肿瘤生长。 目的1：确定葡萄糖如何在远处转移中激发高PGD催化活性。 目的1将研究一系列不寻常的代谢反应如何将葡萄糖转化为代谢产物， 激活PGD。我们最近的工作是第一次在人类中检测到这些反应。那是因为他们只是 在转移性癌细胞中起作用。其功能是支持PGD驱动的转移。 目的2：明确PGD在远处转移中被组成性激活的机制。 目的2将研究激活的PGD如何能够加速葡萄糖消耗和脂肪消耗的速率。 转移性癌细胞中的酸生物合成。这不仅强烈促进转移性肿瘤生长， 还将PGD维持在永久激活状态，该状态在葡萄糖存在时不能被关闭。 目的3：研究PGD如何重编程表观基因组以激活转移性转录组。 目标3将研究PGD如何能够控制“表观基因组”，表观基因组是指小的化学修饰 在染色质内，其调节DNA序列中编码的基因的表达（“转录组”）。 PGD通过加速葡萄糖消耗重编程胰腺癌表观基因组转移细胞 将多余的葡萄糖分解成更小的表观遗传化学物质。这些化学物质被用来增加 许多增强转移性肿瘤生长和赋予治疗抗性的基因的表达。