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

基本信息

项目摘要

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

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 影响因子:
    0
  • 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:
  • 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:
  • 影响因子:
    0
  • 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
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Guido Erwin Michael Eibl其他文献

Guido Erwin Michael Eibl的其他文献

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{{ truncateString('Guido Erwin Michael Eibl', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 17.87万
  • 项目类别:
Chemoprevention and mechanisms of obesity-promoted pancreatic adenocarcinoma
肥胖促进的胰腺癌的化学预防和机制
  • 批准号:
    10398844
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Chemoprevention and mechanisms of obesity-promoted pancreatic adenocarcinoma
肥胖促进的胰腺癌的化学预防和机制
  • 批准号:
    10605224
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Project 1: Adipose tissue inflammation in obesity-promoted pancreatic cancer
项目1:肥胖促进的胰腺癌中的脂肪组织炎症
  • 批准号:
    10398845
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Core 1: Animal and Cell Model Core
核心1:动物和细胞模型核心
  • 批准号:
    10605252
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Core 1: Animal and Cell Model Core
核心1:动物和细胞模型核心
  • 批准号:
    10398850
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Project 1: Adipose tissue inflammation in obesity-promoted pancreatic cancer
项目1:肥胖促进的胰腺癌中的脂肪组织炎症
  • 批准号:
    10605225
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Inflammatory processes In diet-Induced pancreatic cancer promotion
饮食诱发的胰腺癌促进中的炎症过程
  • 批准号:
    8561427
  • 财政年份:
    2013
  • 资助金额:
    $ 17.87万
  • 项目类别:
Animal Core
动物核心
  • 批准号:
    8561432
  • 财政年份:
    2013
  • 资助金额:
    $ 17.87万
  • 项目类别:
Targeting diet-induced promotion of Kras-initiated pancreatic adenocarcinoma
针对饮食诱导的 Kras 引发的胰腺癌的促进作用
  • 批准号:
    8337028
  • 财政年份:
    2012
  • 资助金额:
    $ 17.87万
  • 项目类别:

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肾上腺素能药物治疗AD疗效的临床前试验
  • 批准号:
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    2009
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甲基苯丙胺肾上腺素药物:门诊试验
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    6825160
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