Stress-adaptation in obesity-associated pancreatic cancer

肥胖相关胰腺癌的压力适应

• 批准号: 9577297
• 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/9577297
• 关键词: Acids; Adenocarcinoma Cell; Allografting; Awareness; Biomechanics; Cancer Etiology; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Cytoplasmic Granules; 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; pandemic disease; recruit; statistics; 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％，死亡率增加了 2倍。令人惊讶的是，PDA在最常见的癌症中的死亡率最高，并且 到2020年，它的发生率上升，预计将成为癌症死亡的第二大原因。 通过肥胖来促进PDA的情况尚不清楚。但是，现行的范式是 肥胖相关的压力和炎症标记起着至关重要的作用。因此，应力刺激 （缺氧，氧化，营养 - ，生物力学压力等）被认为是应激的参与 癌细胞的适应性策略以增强其适应性。我们最近证明了非 膜细胞器称为应力颗粒，是一种新型的应力型机制，被动员 KRAS突变体PDA细胞在压力下以增强肿瘤适应性和存活。我们的初步数据提供了 第一线证据表明，压力颗粒对于与肥胖相关的发展至关重要 PDA并确定胰岛素生长因子-1（IGF-1），肥胖驱动癌症的主要介体，是一种有效的 应力颗粒的诱导剂。该提案的目的是阐明压力颗粒的机制 促进与肥胖相关的PDA，并开发抗应激的颗粒化学预防方法。我们 提议：1）确定IGF-1在肥胖相关PDA中的应力颗粒上调中的作用，2） 破译应激颗粒如何促进与肥胖相关的PDA，3）靶向应力颗粒的目标颗粒 肥胖相关PDA的化学预防。总的来说，这些研究可以确定应力颗粒作为一个 肥胖促进压力适应和PDA发展的新型机制，并告知 制定新的化学预防策略。