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

基本信息

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
项目类别：
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

项目摘要

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) 水平升高与罹患此病的风险增加相关胰腺导管腺癌 (PDA)，一种胰腺癌亚型，占诊断的 90% 以上。诊断前长达 10 年即可观察到血浆支链氨基酸 (BCAA) 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) 复合物精心策划。然而，血浆中 BCAA 本身的升高还是它们的分解代谢是造成这种情况的原因？ PDA 尚不清楚。我们已经证明，腺泡细胞（胰腺中的主要细胞群）经常负责 PDA 启动，将优先使用 BCAA 而不是其他底物来产生乙酰辅酶 A。乙酰基- CoA 是能量生产、表观遗传调控和蛋白质生产中的重要代谢物，碳水化合物和脂质。我们发现抑制这些细胞中乙酰辅酶A的产生会抑制PDA 引发。 BCAA 水平升高也被证明会增加胰岛素转录，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，可增加胰腺癌的生长速度。作为胰岛素是在胰腺中产生的，我推测这种局部胰岛素的增加将有助于 PDA 的进展。这该提案旨在确定 BCAA 是否在 PDA 的发生和进展中具有因果作用。我假设 PDA 的启动依赖于 BCAA 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会加剧进展。检验 Aim 中的起始假设 1，我将把我们新的胰腺特异性BCKDH缺失小鼠模型与我们的PDA小鼠模型交叉引发。肿瘤发生率将通过控制饮食中的 BCAA 含量和通过 BCAA 分解代谢的基因消除。将进行 13C 标记实验来评估发育中肿瘤中的支链氨基酸，以确定腺泡细胞使用支链氨基酸启动的机制。为了测试目标 2 中的进展假设，将为小鼠提供富含 BCAA 的饮用水，该水具有研究表明，当植入已建立的胰腺癌细胞系时，会导致肿瘤负荷增加。增加胰岛素对这些发展中肿瘤的影响将通过基因敲除来评估植入前和通过给予药理作用后胰腺癌细胞中的胰岛素受体抑制剂。通过评估肿瘤细胞内在胰岛素信号传导和胰岛素水平的全身效应操纵，我将能够描述 PDA 进展是直接由 PDA 细胞引起还是由其他细胞引起肿瘤微环境中的类型以及 BCAA 分解代谢是否直接影响其中任何一个。这该项目的研究将有助于更好地了解 BCAA 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。