Stress-adaptation in obesity-associated pancreatic cancer

肥胖相关胰腺癌的压力适应

• 批准号: 10415876
• 负责人: Elda Grabocka
• 金额: $ 35.69万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415876
• 关键词: Acids; Allografting; Awareness; Biomechanics; Cancer Etiology; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Data; Death Rate; Development; Diet; Disease; Esters; Genetic; Goals; Growth; Growth Factor; Growth Factor Receptors; Human; Hypoxia; In Vitro; Incidence; Inflammatory; Insulin; Intraepithelial Neoplasia; KRAS2 gene; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Modeling; Molecular; Nutrient; Obese Mice; Obesity; Obesity associated cancer; Organelles; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Play; Resistance; Risk; Risk Factors; Role; STAT protein; Signal Transduction; Stimulus; Stress; Stress and Coping; Survival Rate; Testing; Time; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; cancer cell; cancer diagnosis; cancer risk; coping mechanism; experimental study; fitness; in vivo; inflammatory marker; insulin mediators; mortality; mouse model; mutant; novel; obesity development; pancreatic ductal adenocarcinoma cell; pandemic disease; recruit; statistics; stress granule; transcription factor; tumor; tumorigenesis

ABSTRACT Obesity increases the risk for pancreatic ductal adenocarcinoma (PDA) by ~ 50% and mortality by more than 2-fold. Strikingly, PDA has the highest death rate among the most commonly diagnosed cancers, and with a rising occurrence, it is predicted to become the 2nd leading cause of cancer deaths by 2020. The mechanisms through which obesity promotes PDA are not well understood; however, the prevailing paradigm is that obesity-associated stress and inflammatory markers play an essential role. Accordingly, stress stimuli (hypoxia, oxidative-, nutrient-, biomechanical-stress, etc.) are thought to invoke the engagement of stress- adaptive strategies by cancer cells to enhance their fitness. We have recently demonstrated that non- membranous organelles termed stress granules, are a novel stress-coping machinery that is mobilized by KRAS mutant PDA cells under stress to enhance tumor fitness and survival. Our preliminary data provide the first lines of evidence indicating that stress granules are essential to the development of obesity-associated PDA, and identified insulin growth factor-1 (IGF-1), a principal mediator of obesity-driven cancer, as a potent inducer of stress granules. The goal of this proposal is to elucidate the mechanisms by which stress granules promote obesity-associated PDA and to develop anti-stress granule chemopreventive approaches. We propose to: 1) determine the role of IGF-1 in stress granule upregulation in obesity-associated PDA, 2) decipher how stress granules promote obesity-associated PDA, and 3) target stress granules for the chemoprevention of obesity-associated PDA. Collectively, these studies can establish stress granules as a novel mechanism through which obesity promotes stress adaptation and PDA development, and inform the development of new chemopreventive strategies.

抽象的 肥胖使胰腺导管腺癌 (PDA) 的风险增加约 50%，死亡率增加超过 2倍。引人注目的是，PDA 在最常诊断的癌症中死亡率最高，并且 发病率不断上升，预计到 2020 年将成为癌症死亡的第二大原因。其机制 肥胖如何促进 PDA 尚不清楚；然而，普遍的范式是 与肥胖相关的压力和炎症标志物发挥着重要作用。因此，应激刺激 （缺氧、氧化应激、营养应激、生物力学应激等）被认为会引发应激的参与 癌细胞增强适应性的适应性策略。我们最近证明了非 称为应激颗粒的膜细胞器是一种新型的应激应对机制，由 KRAS 突变 PDA 细胞在应激下可增强肿瘤适应性和存活率。我们的初步数据提供了 第一线证据表明应激颗粒对于肥胖相关疾病的发展至关重要 PDA，并确定胰岛素生长因子-1 (IGF-1)（肥胖引起的癌症的主要介质）是一种有效的 应激颗粒诱导剂。该提案的目标是阐明应力颗粒的机制 促进肥胖相关的 PDA 并开发抗应激颗粒化学预防方法。我们 建议：1) 确定 IGF-1 在肥胖相关 PDA 应激颗粒上调中的作用，2) 破译应激颗粒如何促进肥胖相关的 PDA，以及 3）针对应激颗粒 肥胖相关 PDA 的化学预防。总的来说，这些研究可以将应激颗粒确立为一种 肥胖促进应激适应和 PDA 发育的新机制，并为 制定新的化学预防策略。