The role of branched-chain amino acid metabolism and hyperinsulinemia in pancreatic cancer

支链氨基酸代谢和高胰岛素血症在胰腺癌中的作用

• 批准号: 10387965
• 负责人: Michael Noji
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387965
• 关键词: Ablation; Acetyl Coenzyme A; Acinar Cell; Area; Biological Assay; Branched-Chain Amino Acids; Cancer Etiology; Cancer cell line; Carbohydrates; Catabolism; Cells; Cessation of life; Citric Acid Cycle; Clinical; Complex; Defect; Diabetes Mellitus; Diagnosis; Diazoxide; Diet; Dietary Factors; Duct (organ) structure; Energy-Generating Resources; Enzymes; Essential Amino Acids; Generations; Genetic; Genetic Transcription; Glucose tolerance test; Growth; Growth Factor; Growth and Development function; Human; Hyperinsulinism; Impairment; Implant; In Vitro; Individual; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Investigation; Isoleucine; Keto Acids; Knock-out; Knowledge; Label; Lead; Lesion; Leucine; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Metaplasia; Modeling; Morphology; Mus; Mutate; Mutation; Obesity; Oncogenes; Oxidoreductase; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Plasma; Play; Population; Production; Proteins; Regulation; Risk; Risk Factors; Role; Stress; Sulfonylurea Compounds; Testing; Tumor Burden; Valine; amino acid metabolism; cancer cell; cancer diagnosis; cancer subtypes; cell type; diet-induced obesity; dietary; drinking water; epidemiology study; epigenetic regulation; experimental study; gene therapy; genetic approach; genetic manipulation; implantation; in vivo; inhibitor; insulin sensitivity; insulin signaling; mortality; mouse model; neoplastic; neoplastic cell; novel; pancreas development; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; prevent; promoter; response; tumor; tumor growth; tumor initiation; tumor microenvironment

Project Abstract Elevated levels of branched-chain amino acids (BCAAs) are associated with an increased risk of developing pancreatic ductal adenocarcinoma (PDA), a pancreatic cancer subtype making up over 90% of diagnoses. Increased plasma BCAAs are observed up to 10 years prior to diagnosis, but whether the elevation of these BCAAs directly contributes to PDA is not known. BCAAs are essential amino acids and their catabolism is orchestrated by the rate-limiting enzyme, the branched-chain keto-acid dehydrogenase (BCKDH) complex. However, whether the elevation of the BCAAs themselves in the plasma or their catabolism is responsible for PDA is not yet known. We have shown that acinar cells, the predominant cell population in the pancreas often responsible for PDA initiation, will preferentially use BCAAs over other substrates to produce acetyl-CoA. Acetyl- CoA is an important metabolite in energy production, epigenetic regulation, and the production of proteins, carbohydrates, and lipids. We showed that inhibiting acetyl-CoA production in these cells suppressed PDA initiation. Elevated BCAA levels have also been shown to increase insulin transcription and may lead to hyperinsulinemia. Insulin is a potent anabolic growth factor that increases pancreatic cancer growth rates. As insulin is produced in the pancreas, I hypothesize that this local insulin increase will aid PDA progression. This proposal aims to establish whether BCAAs have a causal role in PDA in both its initiation and its progression. I hypothesize that PDA initiation depends upon BCAAs as an energy source to promote ADM, while PDA progression is potentiated by elevated BCAA levels and hyperinsulinemia. To test the initiation hypothesis in Aim 1, I will cross our novel mouse model of pancreas-specific deletion of BCKDH to our murine model of PDA initiation. Rates of tumor initiation will be assessed through manipulation of the BCAA content in diet and through genetic ablation of BCAA catabolism. 13C labeling experiments will be done to assess metabolic utilization of BCAAs in the developing tumor to identify the mechanism by which acinar cells are using BCAAs for initiation. To test the progression hypothesis in Aim 2, mice will be provided with BCAA-enriched drinking water, which has been shown to lead to heightened tumor burden when implanted with established pancreatic cancer cell lines. The effect of increased insulin in these developing tumors will be assessed through genetic knockouts of the insulin receptor in the pancreatic cancer cells before implantation and by administration of pharmacological inhibitors. By assessing both tumor cell intrinsic insulin signaling and systemic effects of insulin level manipulation, I will be able to delineate whether PDA progression is caused by PDA cells directly or by other cell types in the tumor microenvironment and also whether BCAA catabolism directly impact either of these. The investigations in this project will provide a better understanding of BCAA metabolism and its contribution to hyperinsulinemia and identify vulnerabilities that can be exploited pharmacologically in patients with PDA.

项目摘要 支链氨基酸(BCAA)水平升高与发病风险增加有关 胰腺导管腺癌(PDA)是胰腺癌的一种亚型，占诊断的90%以上。 可在确诊前10年观察到血浆支链氨基酸升高，但这些升高是否 支链氨基酸对PDA的直接贡献尚不清楚。支链氨基酸是必需的氨基酸，它们的分解代谢是 由限速酶，支链酮酸脱氢酶(BCKDH)复合体协调。 然而，无论支链氨基酸本身在血浆中的升高还是它们的分解代谢都是导致 PDA尚不为人所知。我们已经证明，腺泡细胞是胰腺中的主要细胞群，通常 负责PDA的引发，将优先使用支链氨基酸来生产乙酰-辅酶A。乙酰基- 辅酶A是能量产生、表观遗传调节和蛋白质生产的重要代谢物， 碳水化合物和脂类。我们发现，在这些细胞中抑制乙酰辅酶A的产生会抑制PDA 入会仪式。研究还表明，支链氨基酸水平升高也会增加胰岛素转录，并可能导致 高胰岛素血症。胰岛素是一种有效的合成代谢生长因子，可以增加胰腺癌的生长速度。AS 胰岛素是在胰腺中产生的，我假设这种局部的胰岛素增加将有助于PDA的进展。这 该提案旨在确定支链氨基酸在PDA的启动和发展过程中是否具有因果作用。我 假设PDA的启动依赖于支链氨基酸作为促进ADM的能量来源，而PDA 支链氨基酸水平升高和高胰岛素血症加剧了病情进展。在AIM中检验启动假说 1，我将把我们新的胰腺特异性缺失BCKDH的小鼠模型与我们的小鼠PDA模型交叉 入会仪式。肿瘤始发率将通过控制饮食中支链氨基酸含量和通过 支链氨基酸分解代谢的遗传消融。将进行13C标记实验，以评估代谢利用 BCAAs在发展中的肿瘤中的作用，以确定腺泡细胞使用BCAAs启动的机制。 为了验证目标2中的进展假说，将向小鼠提供含有支链氨基酸的饮用水，这种饮用水具有 研究表明，当植入已建立的胰腺癌细胞系时，会导致肿瘤负担增加。 胰岛素增加对这些正在发展中的肿瘤的影响将通过基因敲除 胰岛素受体在胰腺癌细胞种植前和给药后的变化 抑制剂。通过评估肿瘤细胞的内源性胰岛素信号和胰岛素水平的全身效应 操纵，我将能够描绘出PDA进展是由PDA细胞直接引起的还是由其他细胞引起的 肿瘤微环境中的类型，以及支链氨基酸分解代谢是否直接影响其中任何一种。这个 该项目的研究将有助于更好地了解支链氨基酸的代谢及其对 高胰岛素血症，并确定可在PDA患者中进行药理学利用的脆弱性。