Interaction between Chronic Stress and Obesity in Pancreatic Cancer Progression

慢性压力和肥胖在胰腺癌进展中的相互作用

• 批准号: 10409304
• 负责人: Guido Erwin Michael Eibl
• 金额: $ 21.88万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409304
• 关键词: Adrenergic Agents; Amygdaloid structure; Applications Grants; Calories; Cancer Etiology; Cardiovascular Diseases; Catecholamines; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Chronic; Chronic stress; Clinical; Complex; Development; Diet; Disease Progression; Environmental Risk Factor; Event; FDA approved; Fatty acid glycerol esters; Functional disorder; Genes; Genetic Models; Growth; Hematologic Neoplasms; High Fat Diet; High Prevalence; Hormones; Human; Insulin Receptor; Insulin Resistance; KRAS2 gene; KRASG12D; Knowledge; Lead; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolic syndrome; Molecular; Mus; Mutate; Mutation; Neurobiology; Neurons; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oncogenes; Outcome; Outcome Study; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Pharmaceutical Preparations; Prevention; Receptor Signaling; Research; Risk; Signal Pathway; Signal Transduction; Social isolation; Solid; Solid Neoplasm; Stimulant; Stress; Survival Rate; System; Western World; Work; beta-adrenergic receptor; diet-induced obesity; dietary control; epidemiology study; experimental study; human disease; islet stem cells; mouse model; neuropeptide Y; novel; novel strategies; pancreas development; pancreatic cancer cells; pancreatic cancer model; pancreatic cell line; pancreatic ductal adenocarcinoma cell; pre-clinical; preclinical study; prevent; response; stressor; synergism; therapeutic development; tumor; tumor progression; virtual

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.

摘要 胰腺导管腺癌（PDAC）是人类最致命的疾病之一， 存活率只有9%。据估计，PDAC将成为美国癌症相关死亡的第二大原因。 美国在未来十年内。几乎所有PDAC都涉及KRAS癌基因的激活突变， 被认为代表了一个初始事件。虽然突变的Kras是PDAC启动所必需的，但它不是 足以让疾病快速发展。除了肿瘤抑制基因的突变， 与突变的Kras合作，越来越多的人认识到环境因素在人类进化中的重要性。 PDAC进展。在这种情况下，许多流行病学研究将肥胖与以下风险增加联系起来： 发展成PDAC和其他临床上侵袭性的癌症。使用条件性KrasG 12 D的临床前研究 小鼠模型（KC），证明了经受高脂肪热量饮食的KC小鼠变得肥胖，并显示出 PanIN病变和侵袭性PDAC显著增加。还有证据表明，慢性压力会加速 各种肿瘤类型的进展，包括通过β-肾上腺素能信号传导的PDAC。最近的研究 确定了慢性应激、饮食诱导的肥胖（DIO）和胰岛素之间复杂的神经生物学相互作用 阻力本提案的目的是探讨目前在以下方面的知识中存在的重大差距： 压力和饮食诱导肥胖对PDAC进展的相互作用。具体而言，我们建议 研究不同的慢性应激源对PDAC发展的影响，使用转基因的 小鼠模型重现了人类疾病的关键特征。PDAC细胞的机制研究将 阐明介导应激神经递质的促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，导致PDAC 细胞增殖我们提出的中心假设是，慢性应激和饮食诱导的 肥胖有效地加速KC小鼠中Kras引发的前驱病变向侵袭性PDAC的进展。 为了探索这一假设并阐明所涉及的分子机制，我们提出了两个具体目标： 1)使用条件性KrasG 12 D小鼠模型测定PanIN和PDAC的发育，所述条件性KrasG 12 D小鼠模型经受以下处理： 慢性应激源与饮食诱导的肥胖（DIO）相结合，并定义了β- 肾上腺素能受体阻滞。2)确定参与的分子途径 使用人和小鼠胰腺细胞系的儿茶酚胺诱导的PDAC细胞增殖和鉴定 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。的 确定慢性应激与DIO相互作用是PDAC进展的有效刺激物， 阐明了响应于压力和DIO而驱动PDAC发展的信号传导机制， 在本申请中提出的，将具有重大的翻译意义，以发现新的靶标和药物， PDAC预防。