Interaction between Chronic Stress and Obesity in Pancreatic Cancer Progression

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ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human diseases, with overall 5-year survival rate of only 9%. PDAC is estimated to become the 2nd leading cause of cancer-related deaths in the US within the next decade. Virtually all PDACs involve activating mutations in the KRAS oncogene, which are thought to represent an initiating event. Although mutated Kras is necessary for PDAC initiation it is not sufficient for the rapid progression of the disease. In addition to mutation in tumor suppressive genes that collaborate with mutated Kras, there is increasing recognition of the importance of environmental factors in PDAC progression. In this context, many epidemiological studies have linked obesity with increased risk for developing PDAC and other clinically aggressive cancers. Preclinical studies using the conditional KrasG12D mouse model (KC), demonstrated that KC mice subjected to high fat calorie diet became obese and displayed a marked increase in PanIN lesions and invasive PDAC. There is also evidence that chronic stress accelerates the progression of a variety of tumor types, including PDAC through β-adrenergic signaling. Recent studies identified a complex neurobiological interaction between chronic stress, diet-induced obesity (DIO) and insulin resistance. The objective of this proposal is to explore critical gaps in current knowledge concerning the interaction between stress and diet-induced obesity on PDAC progression. Specifically, we propose to examine the impact of different chronic stressors on the development of PDAC using a genetically modified mouse model that recapitulates key features of the human disease. Mechanistic studies in PDAC cells will elucidate the molecular mechanisms that mediate the growth-promoting effects of stress neurotransmitters, including crosstalk between β-adrenergic receptors and insulin receptor signaling pathways leading to PDAC cell proliferation. Our central hypothesis proposed is that interaction between chronic stress and diet-induced obesity potently accelerates the progression of Kras-initiated precursor lesions to invasive PDAC in KC mice. To explore this hypothesis and elucidate the molecular mechanism(s) involved, we propose two Specific Aims: 1) Determine the development of PanINs and PDAC using the conditional KrasG12D mouse model subjected to chronic stressors in combination with diet-induced obesity (DIO) and define the chemopreventive effects of β- adrenergic receptor blocking in each condition. 2) Determine the molecular pathways implicated in catecholamine-induced PDAC cell proliferation using human and mouse pancreatic cell lines and identify crosstalk mechanisms between β-adrenergic receptor and insulin receptor signaling systems. The identification that chronic stress interacting with DIO is a potent stimulant of PDAC progression as well as the elucidation of the signaling mechanisms that drive PDAC development in response to stress and DIO, as proposed in this application, will be of major translational significance to discover novel targets and drugs for PDAC prevention.