The Evolution of PGD addiction in Human Pancreatic Cancer

人类胰腺癌 PGD 成瘾的演变

基本信息

批准号：
10054956
负责人：
Oliver Gene McDonald
金额：
$ 1.81万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2021-01-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054956
关键词：
3-Dimensional Acetyl Coenzyme A Back Blood Circulation Bypass Cancer Etiology Catalysis Cell physiology Cells Cessation of life Chemicals Chromatin Consumption Conversion disorder Coupled DNA Sequence Data Dependence Diagnosis Diffuse 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 Lead Left Link Liver Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolic Pathway Metabolism Modification Mutate NADP Names Neoplasm Metastasis Oxides Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pentosephosphate Pathway Pentoses Phosphogluconate Dehydrogenase Preclinical Testing Primary Neoplasm Production Reaction Recurrence Recycling Research Design Research Methodology Resistance Route Series Specificity TXNIP gene Testing Tissues 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 non-genetic overexpression pancreatic cancer cells pancreatic neoplasm small molecule inhibitor sugar therapeutic target therapy resistant transcriptome treatment strategy tumor growth tumorigenesis

项目摘要

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，对于胰腺癌尤其如此。患者会突然出现数百至数千个转移瘤，并迅速进展以填补该疾病的这一阶段会迅速致死，但人们对此知之甚少，研究也严重不足。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：该提案旨在深入描述一种名为 PGD 的代谢酶如何我们最近发现糖（葡萄糖）会激活 PGD，并且曾经有一次。 PGD 被激活后会强烈刺激肿瘤生长。了解癌细胞如何利用葡萄糖。激活 PGD 以及 PGD 如何促进肿瘤生长非常重要：它可能导致第一个有效的治疗针对疾病进展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，是从死于该疾病的个别患者身上收集的。独特的三维实验。平台将使我们能够研究这些癌症如何在患者体内形成转移性肿瘤。实验将特别关注转移细胞如何将葡萄糖加工成代谢物，从而激活 PGD 酶，以及激活的 PGD 酶如何能够促进转移性肿瘤的生长。目标 1：确定葡萄糖如何在远处转移中促进高 PGD 催化活性。目标 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物我们最近的工作首次在人类中检测到这些反应。它们在转移性癌细胞中发挥作用，支持 PGD 驱动的转移。目标 2：定义 PGD 在远处转移中持续激活的机制。目标 2 将研究活化的 PGD 如何加速葡萄糖消耗和脂肪酸的消耗速度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的生长，而且它还使 PGD 保持在永久激活状态，在葡萄糖存在的情况下无法关闭。目标 3：研究 PGD 如何重新编程表观基因组以激活转移转录组。目标 3 将研究 PGD 如何控制“表观基因组”，即微小的化学修饰染色质内调节 DNA 序列（“转录组”）中编码的基因的表达。 PGD 通过加速转移细胞的葡萄糖消耗来重新编程胰腺癌表观基因组。将多余的葡萄糖分解成更小的表观遗传化学物质，然后使用这些化学物质来增加。许多基因的表达可增强转移性肿瘤的生长并赋予治疗抵抗力。