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.

摘要