Branched chain amino acids and pancreatic cancer

项目摘要 胰腺导管腺癌（PDA）仍然是最难治的癌症类型之一， 五年存活率低于9%令人担忧的是，胰腺癌的发病率 在过去20年中，艾滋病发病率上升，年轻人的发病率尤其急剧上升。 营养不良和肥胖可能是罪魁祸首，肥胖和糖尿病独立地赋予 PDA的风险增加，但机制尚不清楚。 支链氨基酸（BCAA）已经成为一个潜在的重要环节， 饮食、全身代谢和PDA。我们已经在以前的工作和初步证明， 数据表明，BCAA被胰腺贪婪地消耗，它们在胰腺中的作用很大， TCA循环和乙酰辅酶A库。我们最近也发现乙酰辅酶A 代谢在促进胰腺肿瘤的发生中起着关键作用，这导致了以下假设： BCAA代谢是有效的胰腺肿瘤发生所必需的。因此，一个主要目标 这项拨款的一部分将用于测试BCAA在胰腺中促进腺泡细胞增殖的作用。 可塑性和肿瘤形成。我们将使用最先进的体内同位素示踪方法， 阐明支链氨基酸在胰腺中的命运。我们还将采用营养，遗传（使用 两种新的小鼠模型）和药理学方法来定义支链氨基酸的作用 在胰腺功能和肿瘤发生中起重要作用。 与正常胰腺细胞相比，使用支链氨基酸作为燃料源被认为是 抑制胰腺癌的发展。然而，支链氨基酸是一种重要的生物标志物， 在PDA诊断前数年，循环水平升高，表明可能存在 在机制上不同于肿瘤起始。BCAA在肥胖症中也会升高， 糖尿病，它们促进胰岛素分泌和胰岛素抵抗， 高胰岛素血症胰岛素本身作为生长因子促进合成代谢信号传导， PDA细胞中的代谢。因此，我们的第二个主要目标是评估系统的贡献， 支链氨基酸水平和高胰岛素血症对PDA肿瘤生长的影响我们将操纵系统性BCAA 通过营养，遗传和药理学方法来测试对肿瘤的影响 增长然后，我们将询问胰岛素直接对PDA细胞和癌症相关细胞的影响。 成纤维细胞（CAF），沿着降低高胰岛素血症对肿瘤生长的影响。最后， 我们将通过小鼠临床试验测试BCAA代谢靶向的潜力。 这些研究将为深入了解支链氨基酸在多步骤PDA肿瘤发生中的作用提供依据 并可能为这种致命疾病带来新的治疗策略。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) remains one of the most intractable types of cancer, with a 5-year survival rate below 9%. Alarmingly, the incidence of pancreatic cancer is on the rise over the past 20 years, with particularly sharp increases in incidence among young adults. Poor nutrition and obesity are likely culprits, with obesity and diabetes independently conferring increased risk of PDA, but the mechanisms remain unclear. Branched chain amino acids (BCAAs) have emerged as one potentially important link between diet, systemic metabolism, and PDA. We have demonstrated in previous work and preliminary data that BCAAs are avidly consumed by the pancreas, where they contribute prominently to the TCA cycle and to acetyl-CoA pools. We have also recently shown that acetyl-CoA metabolism plays a key role in facilitating pancreatic tumor initiation, leading to the hypothesis that BCAA metabolism is required for efficient pancreatic tumorigenesis. Thus, one major goal of this grant will be to test the role of BCAA catabolism in the pancreas in facilitating acinar cell plasticity and tumor formation. We will use state-of-the-art in vivo isotope tracer approaches to elucidate the fates of BCAAs in the pancreas. We will also employ nutritional, genetic (using two novel mouse models), and pharmacological approaches to define the roles of BCAA catabolism in pancreatic function and tumorigenesis. In contrast to normal pancreatic cells, use of BCAAs as a fuel source is thought to be suppressed as pancreatic cancer develops. Nevertheless, BCAAs are an important biomarker of PDA, with circulating levels elevated years prior to PDA diagnosis, indicating a risk that likely mechanistically differs from that of tumor initiation. BCAAs are also elevated in obesity and diabetes, where they promote insulin secretion and insulin resistance, promoting a hyperinsulinemic state. Insulin itself acts as a growth factor to promote anabolic signaling and metabolism in PDA cells. Our second major goal is thus to evaluate the contribution of systemic BCAA levels and hyperinsulinemia to PDA tumor growth. We will manipulate systemic BCAA levels through nutritional, genetic, and pharmacological approaches to test the impact on tumor growth. We will then query the impact of insulin directly on PDA cells and on cancer-associated fibroblasts (CAFs), along with the impact of reducing hyperinsulinemia on tumor growth. Finally, we will test the potential to target BCAA metabolism through mouse clinical trials. These studies will provide deep insight into the roles of BCAAs in multi-step PDA tumorigenesis and could lead to novel therapeutic strategies for this deadly disease.