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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.

项目总结（摘要）