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: 10612088
• 负责人: Guido Erwin Michael Eibl
• 金额: $ 17.87万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612088
• 关键词: Acceleration; Adrenergic Agents; Adrenergic beta-Antagonists; Amygdaloid structure; Applications Grants; Calories; Cancer Etiology; Cardiovascular Diseases; Catecholamines; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Chronic; Chronic stress; Clinical; Collaborations; 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; 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

项目成果

Statins Inhibit Inflammatory Cytokine Production by Macrophages and Acinar-to-Ductal Metaplasia of Pancreatic Cells.

他汀类药物抑制巨噬细胞的炎症细胞因子产生，胰腺细胞的腺泡到导管化生。

• DOI: 10.1016/j.gastha.2022.04.012
• 发表时间: 2022
• 期刊: Gastro hep advances
• 作者: Ako, Soichiro;Teper, Yaroslav;Ye, Linda;Sinnett-Smith, James;Hines, Oscar J;Rozengurt, Enrique;Eibl, Guido
• 通讯作者: Eibl, Guido

Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice.

• DOI: 10.1038/s41598-023-43498-9
• 发表时间: 2023-09-26
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Teper, Yaroslav;Ye, Linda;Waldron, Richard T.;Lugea, Aurelia;Sun, Xiaoying;Sinnett-Smith, James;Hines, Oscar J.;Pandol, Stephen J.;Rozengurt, Enrique;Eibl, Guido
• 通讯作者: Eibl, Guido

Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids.

他汀类药物可抑制肠细胞中蛋白激酶 D (PKD) 的激活，并阻止 PKD1 诱导的小鼠肠样细胞的生长。

• DOI: 10.1152/ajpcell.00286.2022
• 发表时间: 2023
• 期刊: American journal of physiology. Cell physiology
• 作者: Sinnett-Smith,James;Torres-Marquez,MEugenia;Chang,Jen-Kuan;Shimizu,Yuki;Hao,Fang;Martin,MartinG;Rozengurt,Enrique
• 通讯作者: Rozengurt,Enrique