Interaction between Chronic Stress and Obesity in Pancreatic Cancer Progression

摘要 胰腺导管腺癌(Pdac)是人类最致命的疾病之一，总病死率为5年。 存活率只有9%。据估计，PDAC将成为全球癌症相关死亡的第二大原因 在接下来的十年里。几乎所有的PDAC都涉及激活KRAS癌基因的突变，这些突变是 被认为代表启蒙事件的。虽然突变的Kras是启动PDAC所必需的，但它不是 足以应对疾病的快速发展。除了肿瘤抑制基因突变外， 与突变的Kras合作，人们越来越多地认识到环境因素在 PDAC进展。在这种背景下，许多流行病学研究已经将肥胖与增加的风险联系在一起 发展成PDAC和其他临床侵袭性癌症。使用条件性KrasG12D的临床前研究 小鼠模型(KC)，高脂饮食导致KC小鼠肥胖并表现为 PAIN病变和侵袭性PDAC明显增加。也有证据表明，慢性压力会加速 多种肿瘤类型的进展，包括通过β-肾上腺素能信号传导的动脉导管未闭。最新研究 发现慢性应激、饮食诱导肥胖(DIO)和胰岛素之间存在复杂的神经生物学相互作用 抵抗。这项建议的目标是探索当前知识中关于 压力和饮食诱导的肥胖在PDAC进展中的交互作用。具体来说，我们建议 用基因修饰的方法检测不同慢性应激源对PDAC发展的影响 概括人类疾病主要特征的小鼠模型。PDAC细胞的机制研究将 阐明应激神经递质促进生长作用的分子机制， 包括β-肾上腺素能受体和胰岛素受体信号通路之间的串扰 细胞增殖。我们提出的中心假设是慢性压力和饮食诱导之间的相互作用 肥胖有效地加速了Kras启动的前体病变向KC小鼠侵袭性PDAC的进展。 为了探索这一假说并阐明其中的分子机制(S)，我们提出了两个具体目标： 1)使用条件性KrasG12D小鼠模型确定Panins和PDAC的发育 慢性应激源与饮食诱导的肥胖相结合，并确定β的化学预防作用- 肾上腺素能受体在每种情况下都被阻断。2)确定所涉及的分子途径 儿茶酚胺诱导人和小鼠胰腺细胞系PDAC细胞增殖及鉴定 β-肾上腺素能受体和胰岛素受体信号系统之间的串扰机制。这个 发现慢性应激与DIO的相互作用是PDAC进展的有力刺激因素，以及 阐明驱动PDAC发展的信号机制，以响应应激和DIO，AS 在这项申请中提出的，将对发现新的靶点和药物具有重大的翻译意义 PDAC预防。

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.