权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Defining metabolic adaptations within the PDAC "arid" tumor microenvironment

定义 PDAC“干旱”肿瘤微环境中的代谢适应

基本信息

批准号：
10623158
负责人：
CHI V. DANG
金额：
$ 54.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623158
关键词：
Affect Amino Acids Animal Model Area Back Behavior Biomass Blood Vessels Branched-Chain Amino Acids CRISPR screen Cancer Etiology Cell Culture Techniques Cell Proliferation Cell Separation Cell Survival Cell division Cells Cellular Metabolic Process Cessation of life Citric Acid Cycle Clinical DNA Damage Dependence Diffusion Environment Generations Genes Glucose Goals Growth Heterogeneity Human Hypoxia Immune In Vitro Individual Inter-tumoral heterogeneity Label Lipids Malignant Neoplasms Metabolic Methods Modeling Molecular Myeloid-derived suppressor cells Nutrient Oxidative Phosphorylation Oxygen Pancreatic Ductal Adenocarcinoma Pathway interactions Perfusion Pharmaceutical Preparations Phenotype Production Proliferating Protocols documentation Resources Serum Source System Testing Therapeutic Translations Warburg Effect aerobic glycolysis cancer cell cancer type cell growth chemotherapy coping deprivation experimental study genome wide screen in vivo inhibitor insight macromolecule metabolic abnormality assessment metabolic profile metabolomics neoplastic cell nutrient deprivation pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pancreatic stellate cell refractory cancer response standard of care targeted treatment therapy resistant tumor tumor microenvironment whole genome

项目摘要

PROJECT SUMMARY The goal of our proposal is to identify therapeutic vulnerabilities associated with nutrient-poor conditions in tumors. Pancreatic ductal adenocarcinoma (PDAC) remains a major clinical challenge and is characterized by a dense stroma and paucity of blood vessels. The resulting hypoxia and scarcity of nutrients forces cancer cells to seek alternative sources of nutrients for growth. Paradoxically, cells residing in these nutrient- deprived microenvironments are among the most resistant to therapy as a result of poor drug diffusion and reduced cell proliferation (rendering DNA-damaging agents less effective). To target these cells, therefore, a better understanding of the adaptive mechanisms by which they cope with nutrient deprivation is urgently needed. In preliminary studies, we developed a culture protocol – limiting for oxygen, glucose, amino acids, and serum – to model the “arid conditions” of pancreatic tumors. Under such conditions, tumor cells slow down proliferation and metabolic activity. Using this system, we performed a whole genome CRISPR screen to identify genes required under arid conditions but dispensable under nutrient-replete (“fertile”) conditions. This revealed a strong dependency on the TCA cycle and oxidative phosphorylation for survival, but also suggested that genes involved in many biosynthetic activities (e.g. translation and cell division) are detrimental under arid conditions. Based on these results, we hypothesize that cells survive severe nutrient and oxygen deprivation by maximizing energy generation from limited fuel supplies while minimizing the use of such resources for macromolecule production. We further hypothesize that nutrient and oxygen deprivation alters the dynamic crosstalk between cancer cells and other cells comprising the tumor microenvironment (TME). Importantly, individual tumors may respond to these metabolic changes in different ways, contributing to inter-tumoral heterogeneity. Our proposal will explore these ideas to develop strategies that target therapy-resistant cancer cells residing in these nutrient-deprived niches. Aim 1. Characterize the heterogeneity in metabolic adaptations to arid conditions. Aim 2. Determine how arid conditions influence cellular crosstalk in the TME. Aim 3. Test the activity of metabolic inhibitors against cells in arid conditions in vitro and in vivo.

项目总结