Dietary fatty acids drive pancreatic cancer development

项目总结/摘要 尽管在癌症治疗方面取得了重大进展，但胰腺导管腺癌（PDAC）仍然是第三大癌症。 是美国癌症死亡的主要原因，5年生存率约为10%。肥胖和高脂饮食（HFD） 消耗增加人类队列中的PDAC风险并加速小鼠中的PDAC进展，但 这些关系的机械基础还没有被很好地理解。鉴于世界范围内的快速增长， 肥胖的流行和膳食脂肪的消耗，解读肥胖驱动的PDAC的机制， 广泛影响人类健康。然而，先前饮食研究的翻译相关性受到限制， 在人群和小鼠实验中，脂肪来源和摄入量存在不受控制的变化。因此，我们认为， 特定的膳食脂肪是否以及如何促进胰腺肿瘤发生仍然是关键的未回答的问题 具有重大的社会意义。利用一个独特的等热量面板的HFD不同，只有在脂肪来源，我们 研究发现，高油酸饮食（一种单不饱和脂肪酸， 在PDAC的遗传模型中， 模仿人类疾病的遗传和组织学进展。我们进一步观察到， 这与组织（包括胰腺）中油酸掺入特定磷脂的增加有关。 在这项建议中，我们的目标是测试这一假设，即过量的膳食油酸直接纳入细胞， 胰腺中的脂质来驱动PDAC的发展。目标1中的研究利用了复杂的遗传学， 药理学和饮食方法来调节全身油酸水平， 油酸是促进胰腺肿瘤发生所必需和充分的。目标2中的拟议工作使用 脂质组学分析，以澄清膳食脂肪酸和胰腺脂质组成之间的关系， PDAC进展，并测试特定的所得不饱和溶血磷脂是否驱动肿瘤发生。 最后，目标3中的实验将联合收割机代谢和放射性同位素示踪分析与条件 敲除模型，以破译膳食油酸直接被胰腺吸收的机制 以及胰腺细胞中脂肪酸摄取途径的抑制是否阻断了油酸的促肿瘤作用 酸总之，这些研究将脂肪酸消耗与胰腺脂质组成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变革性的潜力， 有针对性的饮食和药物策略，以预防一种基本上无法治愈的癌症。

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.