Stress-adaptation in obesity-associated pancreatic cancer

摘要 肥胖使胰腺导管腺癌（PDA）的风险增加约50%，死亡率增加超过10%。 2倍。值得注意的是，PDA在最常见的癌症中死亡率最高， 发病率上升，预计到2020年将成为癌症死亡的第二大原因。的机制 肥胖促进PDA的机制尚不清楚;然而，流行的范式是， 肥胖相关的压力和炎症标记物起着重要作用。因此，压力刺激 （缺氧、氧化应激、营养应激、生物力学应激等）被认为是引发了压力的作用 癌细胞的适应性策略来增强它们的适应性。我们最近发现，非... 被称为应激颗粒的膜性细胞器是一种新型的应激应对机制， KRAS突变PDA细胞在应激下增强肿瘤适应性和存活。我们的初步数据提供了 第一批证据表明，压力颗粒是必不可少的发展肥胖相关的 PDA，并确定胰岛素生长因子-1（IGF-1），肥胖驱动的癌症的主要介质，作为一种有效的 应激颗粒诱导剂。该建议的目的是阐明应激颗粒 促进肥胖相关的PDA和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中应激颗粒上调中的作用，2） 破译压力颗粒如何促进肥胖相关的PDA，和3）针对压力颗粒， 肥胖相关PDA的化学预防。总的来说，这些研究可以建立应力颗粒作为 肥胖促进压力适应和PDA发展的新机制，并告知 开发新的化学预防策略。

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.