Stress-adaptation in obesity-associated pancreatic cancer

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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.