课题基金 / 基金详情

Defining metabolic adaptations within the PDAC "arid" tumor microenvironment

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
批准号:
10728412
负责人:
CHI V. DANG
金额:
$46.22万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-05-01 至 2026-04-30

项目摘要

项目成果

CHI V. DANG的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Defining metabolic adaptations within the PDAC "arid" tumor microenvironment
  • 批准号:
    10205608
  • 项目类别:
  • 资助金额:
    $59.87万
  • 财政年份:
    2021
  • 负责人:
    CHI V. DANG
  • 依托单位:
Defining metabolic adaptations within the PDAC "arid" tumor microenvironment
  • 批准号:
    10623158
  • 项目类别:
  • 资助金额:
    $54.47万
  • 财政年份:
    2021
  • 负责人:
    CHI V. DANG
  • 依托单位:
Defining metabolic adaptations within the PDAC "arid" tumor microenvironment
  • 批准号:
    10396617
  • 项目类别:
  • 资助金额:
    $10.35万
  • 财政年份:
    2021
  • 负责人:
    CHI V. DANG
  • 依托单位:
MYC Oncogene Hubsite
  • 批准号:
    6474169
  • 项目类别:
  • 资助金额:
    $6.6万
  • 财政年份:
    2001
  • 负责人:
    CHI V. DANG
  • 依托单位:
国内基金
海外基金
α-酮戊二酸调控ACMSD介导犬尿氨酸通路代谢重编程在年龄相关性听力损失中的作用及机制研究
  • 批准号:
    82371150
  • 项目类别:
    面上项目
  • 资助金额:
    49.00万元
  • 批准年份:
    2023
  • 负责人:
    侯书乐
  • 依托单位:
多囊卵巢综合征中甲酰肽受体2调控小胶质细胞代谢重编程导致GnRH神经元过度激活及HPO轴异常的病理机制研究
  • 批准号:
    82370797
  • 项目类别:
    面上项目
  • 资助金额:
    49.00万元
  • 批准年份:
    2023
  • 负责人:
    陶弢
  • 依托单位:
NPC1调控肾上腺皮质激素分泌影响代谢稳态的机制研究
  • 批准号:
    82370796
  • 项目类别:
    面上项目
  • 资助金额:
    49.00万元
  • 批准年份:
    2023
  • 负责人:
    蒋怡然
  • 依托单位:
衰老上皮细胞FABP4调控HSDL2致脂肪酸代谢失衡在BPH发病中的机制研究
  • 批准号:
    82370774
  • 项目类别:
    面上项目
  • 资助金额:
    49.00万元
  • 批准年份:
    2023
  • 负责人:
    阮渊
  • 依托单位: