Dietary fatty acids drive pancreatic cancer development

膳食脂肪酸促进胰腺癌的发展

基本信息

  • 批准号:
    10735071
  • 负责人:
  • 金额:
    $ 57.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-10 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Despite significant advances in cancer care, pancreatic ductal adenocarcinoma (PDAC) remains the third leading cause of cancer death in the United States with a 5-year survival rate of ~10%. Obesity and high fat diet (HFD) consumption increase PDAC risk in human cohorts and accelerate PDAC progression in mice, but the mechanistic basis for these relationships is not well understood. Given the rapid rise in both the worldwide prevalence of obesity and consumption of dietary fat, deciphering mechanisms of obesity-driven PDAC could broadly impact human health. The translational relevance of prior diet research, however, has been limited by uncontrolled variations in fat source and intake across human populations and mouse experiments. Therefore, whether and how specific dietary fats promote pancreatic tumorigenesis remain critical unanswered questions of great societal importance. Leveraging a unique isocaloric panel of HFDs differing only in fat source, we identified a correlation between consumption of diets high in oleic acid – a monounsaturated fatty acid typically associated with good health – and enhanced tumor development in a genetic model of PDAC that faithfully mimics the genetic and histologic progression of the human disease. We further observed that tumorigenesis correlated with increased incorporation of oleic acid into specific phospholipids in tissues, including the pancreas. In this proposal, we aim to test the hypothesis that excess dietary oleic acid directly incorporates into cellular lipids in the pancreas to drive PDAC development. The studies in Aim 1 utilize sophisticated genetic, pharmacologic, and dietary approaches to modulate systemic oleic acid levels and establish whether excess oleic acid is necessary and sufficient to promote pancreatic tumorigenesis. The proposed work in Aim 2 uses lipidomic analyses to clarify the relationship between dietary fatty acids and pancreatic lipid composition during PDAC progression and tests whether specific resultant unsaturated lysophospholipids drive tumorigenesis. Finally, the experiments in Aim 3 combine metabolic and radioactive isotope tracer analyses with conditional knockout models to decipher the mechanisms by which dietary oleic acid is directly taken up by the pancreas and whether inhibition of fatty acid uptake pathways in pancreatic cells blocks the pro-tumorigenic effects of oleic acid. Together, these studies will link fatty acid consumption to specific changes in pancreatic lipid composition as driving forces in PDAC progression. Results from this work have transformative potential to identify novel targeted dietary and pharmacologic strategies for the prevention of a largely incurable cancer.
项目概要/摘要 尽管癌症治疗取得了重大进展,但胰腺导管腺癌 (PDAC) 仍然是第三大癌症 美国癌症死亡原因,5 年生存率约为 10%。肥胖和高脂肪饮食(HFD) 食用会增加人类 PDAC 风险并加速小鼠 PDAC 进展,但 这些关系的机制基础尚不清楚。鉴于全球范围内的快速崛起 肥胖的流行和膳食脂肪的消耗,破译肥胖驱动的 PDAC 机制可以 广泛影响人类健康。然而,先前饮食研究的转化相关性受到以下因素的限制: 人群和小鼠实验中脂肪来源和摄入量的不受控制的变化。所以, 特定的膳食脂肪是否以及如何促进胰腺肿瘤的发生仍然是一个尚未解答的关键问题 具有重大的社会意义。利用仅脂肪来源不同的独特等热量 HFD 组合,我们 确定了食用高油酸(通常是一种单不饱和脂肪酸)饮食之间的相关性 与良好的健康相关 - 并在 PDAC 遗传模型中增强肿瘤的发展,忠实地 模拟人类疾病的遗传和组织学进展。我们进一步观察到肿瘤发生 与组织(包括胰腺)中油酸与特定磷脂的结合增加相关。 在本提案中,我们的目的是检验以下假设:过量膳食油酸直接融入细胞中。 胰腺中的脂质驱动 PDAC 发育。目标 1 中的研究利用了复杂的遗传、 调节全身油酸水平并确定是否过量的药理学和饮食方法 油酸对于促进胰腺肿瘤的发生是必要且充分的。目标 2 中拟议的工作使用 脂质组学分析可阐明膳食脂肪酸与胰腺脂质成分之间的关​​系 PDAC 进展并测试特定的不饱和溶血磷脂是否驱动肿瘤发生。 最后,目标 3 中的实验将代谢和放射性同位素示踪分析与条件结合起来。 敲除模型破译膳食油酸直接被胰腺吸收的机制 抑制胰腺细胞中的脂肪酸摄取途径是否会阻断油酸的促肿瘤作用 酸。总之,这些研究将脂肪酸消耗与胰腺脂质成分的特定变化联系起来 作为 PDAC 进展的驱动力。这项工作的结果具有识别新颖性的变革潜力 用于预防基本上无法治愈的癌症的有针对性的饮食和药物策略。

项目成果

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Mandar Deepak Muzumdar其他文献

Mandar Deepak Muzumdar的其他文献

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{{ truncateString('Mandar Deepak Muzumdar', 18)}}的其他基金

Multiplexed imaging of chromatin folding and RNA profiles in cancer
癌症中染色质折叠和 RNA 谱的多重成像
  • 批准号:
    10025857
  • 财政年份:
    2020
  • 资助金额:
    $ 57.39万
  • 项目类别:
Elucidating KRAS-specific vulnerabilities in pancreatic cancer
阐明胰腺癌中 KRAS 特异性的脆弱性
  • 批准号:
    9568886
  • 财政年份:
    2016
  • 资助金额:
    $ 57.39万
  • 项目类别:
Elucidating KRAS-specific vulnerabilities in pancreatic cancer
阐明胰腺癌中 KRAS 特异性的脆弱性
  • 批准号:
    9164819
  • 财政年份:
    2016
  • 资助金额:
    $ 57.39万
  • 项目类别:

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