Stress-adaptation in obesity-associated pancreatic cancer

摘要 肥胖使患胰腺导管腺癌(PDA)的风险增加约50%，死亡率增加超过 2折。引人注目的是，在最常见的诊断癌症中，PDA的死亡率最高，而且 随着发病率的上升，预计到2020年，它将成为癌症死亡的第二大原因。其作用机制 肥胖是如何促进PDA的还不是很清楚；然而，流行的范式是 肥胖相关的压力和炎症标记物起着至关重要的作用。因此，应激刺激 (低氧、氧化、营养、生物机械应激等)被认为引发了压力的介入- 通过癌细胞的适应性策略来增强它们的适应性。我们最近已经证明了非 膜细胞器被称为应激颗粒，是一种新型的应激应对机制，由 KRAS突变型PDA细胞在应激状态下增强肿瘤适合性和存活率。我们的初步数据提供了 第一线证据表明，压力颗粒对肥胖相关疾病的发展是必不可少的 PDA，并确定胰岛素生长因子-1(IGF-1)是肥胖症驱动的癌症的主要媒介，是一种有效的 应激颗粒诱导剂。这项提议的目的是阐明应激颗粒 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) 破译压力颗粒如何促进肥胖相关的PDA，以及3)针对 肥胖相关PDA的化学预防。总的来说，这些研究可以建立压力颗粒作为一种 肥胖通过促进压力适应和PDA发展的新机制，并告知 制定新的化学预防策略。

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.